bims-meract 2025-02-16 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–02–16
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

ANO7 expression in the prostate modulates mitochondrial function and lipid metabolism.
ANGPTL3 regulates the peroxisomal translocation of SmarcAL1 in response to cell growth states.
ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production.
Acyl-CoA thioesterase 8 induces gemcitabine resistance via regulation of lipid metabolism and antiferroptotic activity in pancreatic ductal adenocarcinoma.
TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism.
HSP90 co-regulates the formation and nuclear distribution of the glycolytic output complex to promote resistance and poor prognosis in gastric cancer patients.
AURKB inhibition induces rhabdomyosarcoma apoptosis and ferroptosis through NPM1/SP1/ACSL5 axis.
Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth.
Inhibition of tubular epithelial cells ferroptosis alleviates renal interstitial fibrosis by reducing lipid hydroperoxides and TGF-β/Smad signaling.
Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis.
Stabilization of RUNX1 Induced by O-GlcNAcylation Promotes PDGF-BB-Mediated Resistance to CDK4/6 Inhibitors in Breast Cancer.
Thioredoxin related transmembrane protein 1acts as a prognostic indictor and promotes proliferation and TMZ resistance of lower-grade glioma.
Treatment of dexamethasone and lenalidomide-resistant multiple myeloma via RAD51 degradation using PROTAC and synergistic effects with chemotherapy.
CPT1A mediates succinylation of LDHA at K318 site promoteing metabolic reprogramming in NK/T-cell lymphoma nasal type.
Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer.
Gefitinib induces apoptosis in Caco-2 cells via ER stress-mediated mitochondrial pathways and the IRE1α/JNK/p38 MAPK signaling axis.
Phillyrin regulates the JAK2/STAT3 signaling pathway by inhibiting TOP2A expression to accelerate ferroptosis in hepatocellular carcinoma.
Synergistic anticancer effects of mitochondria-targeting peptide combined with paclitaxel in breast cancer cells: a preclinical study.
KSR1 mediates small-cell lung carcinoma tumor initiation and cisplatin resistance.
Nudix Hydrolase 13 Impairs the Initiation of Colorectal Cancer by Inhibiting PKM1 ADP-Ribosylation.
HDAC2-Mediated METTL3 Delactylation Promotes DNA Damage Repair and Chemotherapy Resistance in Triple-Negative Breast Cancer.
Lactoferrin-Encapsulated Dichloroacetophenone (DAP) nanoparticles enhance drug delivery and anti-tumor efficacy in prostate cancer.
DLGAP5 upregulates E2F1 to promote prostate adenocarcinoma neuroendocrine differentiation.
ZCCHC4 regulates esophageal cancer progression and cisplatin resistance through ROS/c-myc axis.
SIRT3 regulates PFKFB3-mediated glycolysis to attenuate cisplatin-induced ototoxicity both in vivo and in vitro.

Cell Commun Signal. 2025 Feb 08. 23(1): 71

ANO7 expression in the prostate modulates mitochondrial function and lipid metabolism.

Christoffer Löf, Nasrin Sultana, Neha Goel, Samuel Heron, Gudrun Wahlström, Andrew House, Minna Holopainen, Reijo Käkelä, Johanna Schleutker.

   BACKGROUND: Prostate cancer (PrCa) is a significant health concern, ranking as the second most common cancer in males globally. Genetic factors contribute substantially to PrCa risk, with up to 57% of the risk being attributed to genetic determinants. A major challenge in managing PrCa is the early identification of aggressive cases for targeted treatment, while avoiding unnecessary interventions in slow-progressing cases. Therefore, there is a critical need for genetic biomarkers that can distinguish between aggressive and non-aggressive PrCa cases. Previous research, including our own, has shown that germline variants in ANO7 are associated with aggressive PrCa. However, the function of ANO7 in the prostate remains unknown.
METHODS: We performed RNA-sequencing (RNA-seq) on RWPE1 cells engineered to express ANO7 protein, alongside the analysis of a single-cell RNA-sequencing (scRNA-seq) dataset and RNA-seq from prostate tissues. Differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted to identify key pathways. Additionally, we assessed oxidative phosphorylation (OXPHOS), glycolysis, and targeted metabolomics. Image analysis of mitochondrial morphology and lipidomics were also performed to provide further insight into the functional role of ANO7 in prostate cells.
RESULTS: ANO7 expression resulted in the downregulation of metabolic pathways, particularly genes associated with the MYC pathway and oxidative phosphorylation (OXPHOS) in both prostate tissue and ANO7-expressing cells. Measurements of OXPHOS and glycolysis in the ANO7-expressing cells revealed a metabolic shift towards glycolysis. Targeted metabolomics showed reduced levels of the amino acid aspartate, indicating disrupted mitochondrial function in the ANO7-expressing cells. Image analysis demonstrated altered mitochondrial morphology in these cells. Additionally, ANO7 downregulated genes involved in fatty acid metabolism and induced changes in lipid composition of the cells, characterized by longer acyl chain lengths and increased unsaturation, suggesting a role for ANO7 in regulating lipid metabolism in the prostate.
CONCLUSIONS: This study provides new insights into the function of ANO7 in prostate cells, highlighting its involvement in metabolic pathways, particularly OXPHOS and lipid metabolism. The findings suggest that ANO7 may act as a key regulator of cellular lipid metabolism and mitochondrial function in the prostate, shedding light on a previously unknown aspect of ANO7's biology.

Keywords:  ANO7; Glycolysis; Lipid metabolism; MYC; Mitochondria; OXPHOS; Prostate cancer

DOI:  https://doi.org/10.1186/s12964-025-02081-7
Sci Rep. 2025 Feb 11. 15(1): 5036

ANGPTL3 regulates the peroxisomal translocation of SmarcAL1 in response to cell growth states.

Taylor Hanta Nagai, Taiji Mizoguchi, Yanyan Wang, Amy Deik, Kevin Bullock, Clary B Clish, Yu-Xin Xu.

Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.

DOI: https://doi.org/10.1038/s41598-025-89552-6
Adv Sci (Weinh). 2025 Feb 14. e2416467

ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production.

Cuimiao Zheng, Hao Tan, Gang Niu, Xi Huang, Jingyi Lu, Siqi Chen, Haoyuan Li, Jiayu Zhu, Zhou Zhou, Manman Xu, Chaoyun Pan, Junxiu Liu, Jie Li.

  Lactate derived from aerobic glycolysis is crucial for DNA damage repair and chemoresistance. Nevertheless, it is frequently noted that cancer cells depend on glutaminolysis to replenish essential metabolites. Whether and how glutaminolysis might enhance lactate production and facilitate DNA repair in cancer cells remains unknown. Here, it is shown that malate enzyme 2 (ME2), which metabolizes glutamine-derived malate to pyruvate, contributes to lactate production and chemotherapy resistance in ovarian cancer. Mechanistically, chemotherapy reduces the expression of glucose transporters and impairs glucose uptake in cancer cells. The resultant decrease in intracellular glucose levels triggers the acetylation of ME2 at lysine 156 by ACAT1, which in turn potentiates ME2 enzyme activity and facilitates lactate production from glutamine. ME2-derived lactate contributes to the development of acquired chemoresistance in cancer cells subjected to prolonged chemotherapy, primarily by facilitating the lactylation of proteins involved in homologous recombination repair. Targeting ACAT1 to inhibit ME2 acetylation effectively reduced chemoresistance in both in vitro and in vivo models. These findings underscore the significance of acetylated ME2-mediated lactate production from glutamine in chemoresistance, particularly under conditions of reduced intracellular glucose within cancer cell, thereby complementing the Warburg effect and offering new perspectives on the metabolic links to chemotherapy resistance.

Keywords:  ME2; acetylation; lactylation; platinum resistance

DOI:  https://doi.org/10.1002/advs.202416467
Acta Pharmacol Sin. 2025 Feb 12.

Acyl-CoA thioesterase 8 induces gemcitabine resistance via regulation of lipid metabolism and antiferroptotic activity in pancreatic ductal adenocarcinoma.

Bo-Rui Li, Ting Wang, Hai-Feng Hu, Di Wu, Chen-Jie Zhou, Shun-Rong Ji, Qi-Feng Zhuo, Zheng Li, Zhi-Liang Wang, Gui-Xiong Fan, De-Sheng Jing, Chong-Yuan Yu, Yi Qin, Xue-Min Chen, Jun-Feng Xu, Xiao-Wu Xu.

Pancreatic ductal adenocarcinoma (PDAC) comprises a group of highly malignant tumors of the pancreas. Metabolic reprogramming in tumors plays a pivotal role in promoting cancer progression. However, little is known about the metabolic alterations in tumors that drive cancer drug resistance in patients with PDAC. Here, we identified acyl-CoA thioesterase 8 (ACOT8) as a key player in driving PDAC gemcitabine (GEM) resistance. The expression of ACOT8 is significantly upregulated in GEM-resistant PDAC tissues and is closely associated with poor survival in patients with PDAC. Gain- and loss-of-function studies have shown that ACOT8 drives PDAC GEM resistance both in vitro and in vivo. Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. The combination of orlistat, an ACOT8 inhibitor, and GEM significantly inhibited tumor growth in PDAC organoid and mouse models. This study reveals the biological importance of ACOT8 and provides a potential combination therapy for treating patients with advanced GEM-resistant PDAC.

DOI: https://doi.org/10.1038/s41401-025-01477-y
J Clin Invest. 2025 Feb 11. pii: e178550. [Epub ahead of print]

TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism.

Yu Zeng, Liqian Zhao, Kunlin Zeng, Ziling Zhan, Zhengming Zhan, Shangbiao Li, Hongchao Zhan, Peng Chai, Cheng Xie, Shengfeng Ding, Yuxin Xie, Li Wang, Cuiying Li, Xiaoxia Chen, Daogang Guan, Enguang Bi, Jian-You Liao, Fan Deng, Xiaochun Bai, Ye Song, Aidong Zhou.

  Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by dysregulated metabolism. Increased fatty acid oxidation (FAO) protects tumor cells from lipid peroxidation-induced cell death, although the precise mechanisms involved remain unclear. Herein, we report that loss of tumor necrosis factor receptor-associated factor 3 (TRAF3) in GBM critically regulates lipid peroxidation and tumorigenesis by controlling the oxidation of polyunsaturated fatty acids (PUFAs). TRAF3 is frequently repressed in GBM due to promoter hypermethylation. TRAF3 interacts with enoyl-CoA hydratase 1 (ECH1), an enzyme catalyzing the isomerization of unsaturated fatty acids (UFAs), and mediates K63-linked ubiquitination of ECH1 at Lys214. ECH1 ubiquitination impedes TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promotes the oxidation of UFAs, preferentially the PUFAs, and limits lipid peroxidation. Overexpression of TRAF3 enhances the sensitivity of GBM to ferroptosis and anti-PD-L1 immunotherapy in mice. Thus, the TRAF3-ECH1 axis plays a key role in the metabolism of PUFAs, and is crucial for lipid peroxidation damage and immune elimination in GBM.

Keywords:  Brain cancer; Cancer immunotherapy; Cell biology; Fatty acid oxidation; Metabolism

DOI:  https://doi.org/10.1172/JCI178550
J Transl Med. 2025 Feb 10. 23(1): 172

HSP90 co-regulates the formation and nuclear distribution of the glycolytic output complex to promote resistance and poor prognosis in gastric cancer patients.

Gaigai Shen, Shiya Liu, Yuanting Cao, Zihao Chen, Guanghui Wang, Long Yu, Lixin Sun, Yuliang Ran.

   BACKGROUND: Resistance to treatment is a critical factor contributing to poor prognosis in gastric cancer patients. HSP90 has emerged as a promising therapeutic target; however, its role in regulating tumor metabolic pathways, particularly glycolysis, remains poorly understood, which limits its clinical application.
METHODS: We identified proteins that directly interact with HSP90 using immunoprecipitation (IP) followed by mass spectrometry. The relationship between HSP90 and glycolysis was further investigated through transcriptomic analyses and in vitro experiments. Mechanistic insights were obtained through mass spectrometry, co-immunoprecipitation (Co-IP) assays, drug sensitivity tests, and bioinformatics analyses. Additionally, we developed a scoring system based on transcriptomic data to evaluate its prognostic significance and association with treatment resistance in gastric cancer patients.
RESULTS: Our multi-omics and in vitro studies revealed that HSP90 regulates glycolysis and influences the stemness properties of gastric cancer cells. Mechanistically, HSP90 facilitates the assembly of a glycolytic multi-enzyme complex, termed the HGEO complex, which enhances glycolytic metabolism. Mechanistically, HSP90 facilitates the formation of a multienzyme complex comprising key enzymes including PGK1, PKM2, ENO1, and LDHA, thereby facilitating the production of the final glycolytic products. We refer to this as the "HSP90-Glycolytic Output Complex" (HGEO Complex). We quantified this phenomenon with a scoring system (HGScore), finding that patients with a high HGScore exhibited more malignant signatures, increased resistance to treatment, and poorer prognoses. Furthermore, we demonstrated that the HGEO complex is localized in the nucleus, regulated by the nuclear lamina protein LMNA, which further contributes to treatment resistance and adverse outcomes. In vitro experiments indicated that inhibiting the formation of this complex sensitizes gastric cancer cells to chemotherapy.
CONCLUSION: Our findings suggest that HSP90 and LMNA mediated the formation and nuclear localization of the HGEO complex, thereby enhancing the malignant traits and resistance mechanisms in gastric cancer. Targeting this pathway may offer a novel therapeutic strategy to improve treatment outcomes.

Keywords:  Glycolytic multi-enzyme complex; HSP90; LMNA; Nuclear distribution; Tumor resistance

DOI:  https://doi.org/10.1186/s12967-025-06196-w
JCI Insight. 2025 Feb 10. pii: e182429. [Epub ahead of print]10(3):

AURKB inhibition induces rhabdomyosarcoma apoptosis and ferroptosis through NPM1/SP1/ACSL5 axis.

Huimou Chen, Mengzhen Li, Yu Zhang, Mengjia Song, Yi Que, Juan Wang, Feifei Sun, Jia Zhu, Junting Huang, Juan Liu, Jiaqian Xu, Suying Lu, Yizhuo Zhang.

  Rhabdomyosarcoma (RMS) is one of the most common solid tumors in children and adolescents. Patients with relapsed/refractory RMS have limited treatment options, highlighting the urgency for the identification of novel therapeutic targets for RMS. In the present study, aurora kinase B (AURKB) was found to be highly expressed in RMS and associated with unfavorable prognosis of patients. Functional experiments indicated that inhibition of AURKB significantly reduced RMS cell proliferation, induced apoptosis and ferroptosis, and suppressed RMS growth in vivo. The highly expressed AURKB in RMS contributes to the apoptosis and ferroptosis resistance of tumor cells through the nucleophosmin 1 (NPM1)/Sp1 transcription factor (SP1)/acyl-CoA synthetase long-chain family member 5 (ACSL5) axis. Furthermore, inhibition of AURKB exerted an anti-RMS effect together with vincristine both in vitro and in vivo, with tolerable toxicity. The above findings provide insights we believe are new into the tumorigenesis of RMS, especially with regard to apoptosis or ferroptosis resistance, indicating that AURKB may be a potential target for clinical intervention in patients with RMS.

Keywords:  Oncogenes; Oncology

DOI:  https://doi.org/10.1172/jci.insight.182429
Cell Death Dis. 2025 Feb 13. 16(1): 95

Mitochondrial carrier homolog 2 is important for mitochondrial functionality and non-small cell lung cancer cell growth.

Yong Zhao, Siyang Wu, Guohong Cao, Peidong Song, Chang-Gong Lan, Lin Zhang, Yong-Hua Sang.

Discovering new molecular targets for non-small cell lung cancer (NSCLC) is critically important. Enhanced mitochondrial function can promote NSCLC progression by enabling metabolic reprogramming, resistance to apoptosis, and increased cell proliferation. Mitochondrial carrier homolog 2 (MTCH2), located in the outer mitochondrial membrane, is pivotal in regulating mitochondrial activities. This study examines MTCH2 expression and its functional role in NSCLC. Bioinformatic analysis showed that MTCH2 is overexpressed in NSCLC tissues, correlating with poor prognosis and other key clinical parameters of the patients. In addition, single-cell sequencing data revealed higher MTCH2 expression levels in cancer cells of NSCLC tumor mass. Moreover, MTCH2 is also upregulated in locally-treated NSCLC tissues and multiple primary/established human NSCLC cells. In various NSCLC cells, silencing MTCH2 via targeted shRNA or knockout (KO) using the CRISPR/Cas9 method significantly hindered cell proliferation, migration and invasion, while inducing apoptosis. MTCH2 knockdown or KO robustly impaired mitochondrial function, as indicated by reduced mitochondrial respiration, decreased complex I activity, lower ATP levels, lower mitochondrial membrane potential (mitochondrial depolarization), and increased reactive oxygen species (ROS) production. Conversely, ectopic overexpression of MTCH2 in primary NSCLC cells enhanced mitochondrial complex I activity and ATP production, promoting cell proliferation and migration. In vivo, the intratumoral injection of MTCH2 shRNA adeno-associated virus (aav) impeded the growth of subcutaneous xenografts of primary NSCLC cells in nude mice. In MTCH2 shRNA aav-injected NSCLC xenograft tissues, there was decreases in MTCH2 expression, mitochondrial complex I activity, ATP content, and the glutathione (GSH)/glutathione disulfide (GSSG) ratio, but increase in thiobarbituric acid reactive substances (TBAR) activity. Additionally, MTCH2 silencing led to reduced Ki-67 staining but increased apoptosis in NSCLC xenografts. Collectively, these findings demonstrate that overexpressed MTCH2 promotes NSCLC cell growth potentially through the maintenance of mitochondrial hyper-function, highlighting MTCH2 as a novel and promising therapeutic target for treating this disease.

DOI: https://doi.org/10.1038/s41419-025-07419-0
Cell Commun Signal. 2025 Feb 11. 23(1): 81

Inhibition of tubular epithelial cells ferroptosis alleviates renal interstitial fibrosis by reducing lipid hydroperoxides and TGF-β/Smad signaling.

Yuting Chen, Yue Dai, Yi Huang, Le Zhang, Cuntai Zhang, Hongyu Gao, Qi Yan.

   BACKGROUND: Ferroptosis is a non-apoptotic form of regulated cell death that involves an imbalance in the homeostasis of two elements: iron and lipid hydroperoxides. The accumulation of lipid hydroperoxide serves as a key trigger for initiating ferroptosis. Recent studies have identified ferroptosis as a critical pathophysiology contributing to kidney disease progression. However, the specific mechanisms underlying the role of ferroptosis in chronic kidney disease (CKD) have not been elucidated.
METHODS: Tubular epithelial cells (TECs) ferroptosis was evaluated in unilateral ureteral obstruction (UUO) models and in TGF-β-treated HK-2 cells to explore the relationship between ferroptosis and fibrosis. Ferroptosis inhibitors (ferrostatin-1) and TECs-targeted glutathione peroxidase 4 (GPX4) overexpression in vivo and in vitro were used to investigate the effect and mechanism of TECs ferroptosis on fibrosis progression.
RESULTS: Our findings indicate that ferroptosis is persistently activated during various states of the UUO model. As the results, ferroptosis was identified as a core facilitator of renal interstitial fibrosis in TECs during UUO. The reduction in TECs ferroptosis significantly ameliorated renal fibrosis and maintained the structure in the proximal tubules. Persistent activation of TECs ferroptosis effectively aggravated fibrosis progression through the TGF-β/Smad pathway.
CONCLUSIONS: Inhibiting ferroptosis effectively rescues the accumulation of profibrotic cytokines, thereby alleviating renal fibrosis. The profibrotic mechanism of ferroptosis is closely related to the TGF-β/Smad pathway, and targeting ferroptosis and increasing GPX4 expression could be an effective strategy for treating CKD.

Keywords:  Ferroptosis; Lipid hydroperoxide; Pro-fibrotic factors; Renal interstitial fibrosis; Tubular epithelial cells

DOI:  https://doi.org/10.1186/s12964-025-02068-4
Redox Biol. 2025 Feb 03. pii: S2213-2317(25)00041-2. [Epub ahead of print]80 103528

Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis.

Ning Jin, Yi-Yu Qian, Xiao-Fei Jiao, Zhen Wang, Xin Li, Wen Pan, Jin-Kai Jiang, Pu Huang, Si-Yuan Wang, Ping Jin, Qing-Lei Gao, Dan Liu, Yu Xia.

  Ovarian cancer (OC) is prone to peritoneum or omentum dissemination, thus giving rise to the formidable challenge of unresectable surgery and a dismal survival rate. Although niraparib holds a pivotal role in the maintenance treatment of OC, its effect on suppressing metastases during primary intervention remains enigmatic. Recently, we initiated a prospective clinical study (NCT04507841) in order to evaluate the therapeutic efficacy of neoadjuvant niraparib monotherapy for advanced OC with homologous recombination deficiency. An analysis of patient tumor burden before and after the niraparib challenge showed a remarkable vulnerability of OC intraperitoneal metastases to niraparib exposure. This killing capacity of niraparib was closely associated with the accumulation of fatty acids within the abdomen, which was confirmed by the increased susceptibility of tumor cells to niraparib treatment in the presence of fatty acids. In the context of abundant fatty acids, niraparib elevated intracellular levels of fatty acids and lipid peroxidation, leading to subsequent tumor cell ferroptosis in a p53 and BRCA-independent manner. Notably, under niraparib exposure, a critical fatty acid transporter CD36 was dramatically upregulated in tumors, facilitating excessive uptake of fatty acids. Pharmacological inhibition of either ferroptosis or CD36 impaired the anti-tumor activity of niraparib both in vitro and in murine intraperitoneal ID8 tumor models. Our findings demonstrate ferroptosis as a novel mechanism underlying the regression of OC metastases induced by niraparib, thereby offering tantalizing prospects for the frontline application of this agent in the management of OC.

Keywords:  CD36; Fatty acid; Ferroptosis; Intraperitoneal metastases; Niraparib; Ovarian cancer

DOI:  https://doi.org/10.1016/j.redox.2025.103528
Cancer Res. 2025 Feb 12.

Stabilization of RUNX1 Induced by O-GlcNAcylation Promotes PDGF-BB-Mediated Resistance to CDK4/6 Inhibitors in Breast Cancer.

Shuyan Zhou, Yi Zhang, Julie Belmar, Chunyan Hou, Yaqin Zhang, Changmin Peng, Yunxiao Meng, Zhuqing Li, Muhammad Jameel Mughal, Yanjun Gao, Edward Seto, Min Shen, Matthew D Hall, Junfeng Ma, Cynthia X Ma, Shunqiang Li, Wenge Zhu.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial in regulating cell cycle progression and cancer development. Targeting CDK4/6 has shown considerable promise in treating various cancers, including breast cancer. Despite significant therapeutic efficacy, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial hurdle in clinical practice. Using a co-culture system, cytokine array, and quantitative high-throughput combinatorial screening (qHTCS), we discovered a mechanism by which the RUNX1-PDGF-BB axis regulates palbociclib resistance in breast cancer cells. Specifically, RUNX1 functioned as a transcription factor to drive expression of PDGF-BB, leading to resistance to palbociclib by enhancing the Akt pathway and suppressing senescence. Furthermore, in resistant cells, RUNX1 was O-GlcNAcylated at serine 252 (S252) by OGT, resulting in the stabilization of RUNX1 by preventing ubiquitin-mediated degradation. Inhibition of the RUNX1-PDGF-BB axis by specific inhibitors overcame palbociclib resistance both in vitro and in vivo. Notably, the RUNX1-PDGF-BB axis was upregulated in resistant patient-derived xenograft (PDX) lines and in breast cancer patients following treatment with CDK4/6i. These findings not only unveil O-GlcNAcylation-mediated activation of a RUNX1-PDGF-BB pathway as a driver of palbociclib resistance but also provide clinical evidence supporting the repurposing of FDA-approved PDGFR inhibitors as a therapeutic strategy to treat CDK4/6i-resistant breast cancer patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2492
Sci Rep. 2025 Feb 12. 15(1): 5246

Thioredoxin related transmembrane protein 1acts as a prognostic indictor and promotes proliferation and TMZ resistance of lower-grade glioma.

Hongyan Hui, Fang Zhou, Sujuan Pei, Wenyan Zhou, Jie Shang, Pengwei Wang, Zhijian Deng, Xiang Zhou.

  Thioredoxin Related Transmembrane Protein 1 (TMX1) encodes a thiol-disulfide oxidoreductase and regulates cleavage, formation, or isomerization of disulfide bonds among cysteine residues in proteins. Using bioinformatic analysis, we firstly prove TMX1 is significantly upregulated in lower-grade gliomas (LGGs) and associated with poor prognosis of LGG patients. Besides, it's also highly expressed in higher WHO grade, 1p/19q non-co-deleted and isocitrate dehydrogenase (IDH) wildtype LGGs, thus we established a TMX1-based nomogram model, which exhibits a strong and stable predictive ability in the prognosis of LGG patients. Then, we also noticed that TMX1 was significantly associated with the immune cell infiltrations in LGGs, especially in B cell, CD8+ T cell, CD4+T cell, dendritic cell, macrophage and neutrophil. Meanwhile, it was also highly correlated to the expressions of MKI67, PCNA, PROM1 and SOX2 in LGGs, and that higher TMX1 LGGs showed a stronger resistance to temozolomide (TMZ). Finally, in our in vitro and in vivo experiments, we verified that TMX1 is highly expressed in LGG patients clinically, and it not only regulates the proliferative ability of SW1088 and SW1783 cells both in vitro and in vivo, it can also be inhibited to increase the TMZ therapy sensitivity in vivo. These results revealed that TMX1 acts as a strong prognostic biomarker in LGGs, and targeting TMX1 can be an efficient way to increase the TMZ therapy in LGG patients.

Keywords:  Cell proliferation; Lower grade glioma (LGG); Temozolomide resistance; Thioredoxin related transmembrane protein 1 (TMX1)

DOI:  https://doi.org/10.1038/s41598-025-89908-y
J Physiol Pharmacol. 2024 Dec;75(6):

Treatment of dexamethasone and lenalidomide-resistant multiple myeloma via RAD51 degradation using PROTAC and synergistic effects with chemotherapy.

S Kim, I Hwang, Y K Kim, D S Kim, Y J Choi, E-B Jeung.

Multiple myeloma (MM) is a clonal B-cell malignancy arising from plasma cells in the bone marrow that can lead to various symptoms such as bone pain and fractures, anemia, renal failure and repeated infection. Treatment involves steroids, chemotherapy, targeted therapy and stem cell transplantation. On the other hand, resistance to these treatments often develops, particularly in relapsed/refractory MM, necessitating new strategies. This study examined the degradation of RAD51 recombinase (RAD51) in MM cell lines resistant to existing treatments using proteolysis targeting chimeras (PROTACs). Resistant cell lines were established by exposing human B lymphoblast cell lines, MM.1S and MM.1R, to increasing doses of lenalidomide or pomalidomide. Targeted RAD51 degradation (TRD) 2, a novel PROTAC targeting RAD51, reduced the RAD51 protein levels and cell proliferation. TRD2, combined with chemotherapy drug cisplatin, showed enhanced efficacy in cell proliferation compared to single-agent treatment. In vivo studies confirmed the synergistic effects of TRD2 and cisplatin in inhibiting tumor growth in lenalidomide-resistant MM.1R xenograft models without significant toxicity. MM cells exhibit increased RAD51 expression as they develop resistance to chemotherapy. This study shows that targeting RAD51 with TRD2 enhances the efficacy of DNA-damaging treatments, providing a promising approach for overcoming drug resistance in MM. The inhibition of RAD51 combined with cisplatin therapy can maximize the treatment efficacy of MM patients resistant to dexamethasone and lenalidomide. Nevertheless, further research will be needed to explore the clinical applications of these findings.

DOI: https://doi.org/10.26402/jpp.2024.6.10
Cell Biol Toxicol. 2025 Feb 11. 41(1): 42

CPT1A mediates succinylation of LDHA at K318 site promoteing metabolic reprogramming in NK/T-cell lymphoma nasal type.

Hao Tian, Yi Ge, Jianjun Yu, Xing Chen, Honghan Wang, Xu Cai, Zhenfeng Shan, Liang Zuo, Yan Liu.

  Carnitine palmitoyltransferase 1A (CPT1A), a succinylating enzyme, is highly expressed in various malignant tumors and promotes tumor progression. Succinylation is a posttranslational modification that has been reported in various diseases, but its role in NK/T-Cell lymphoma nasal type (ENKTL-NT) remains underexplored. In this study, bioinformatics analysis showed that glycolytic is a major metabolic pathway in ENKTL-NT as the expression of many glycolytic related kinases are increased. CPT1A probably mediates glycolytic process, as indicated by GO-enrichment analysis. Studies showed that CPT1A was upregulated in ENKTL-NT tissues, and that high CPT1A expression was associated with poor prognosis of ENKTL-NT. CPT1A promoted the proliferation, colony formation, invasion and glycolytic process of ENKTL-NT cells and suppresses apoptosis. Mechanistically, CPT1A promotes succinylation of LDHA at lysine 318 (K318), which increase the protein stability and the final protein level of LDHA. Both knockdown and mutation (K318R) of LDHA abolished the cancer-promoting effects of CPT1A in ENKTL-NT. In all, this study reveals the mechanism underlying the cancer-promoting effects of CPT1A via inducing LDHA succinylation and metabolic reprogramming in ENKTL-NT. These findings might provide potential targets for the diagnosis or therapy of ENKTL-NT.

Keywords:  CPT1A; ENKTL-NT; Glycolytic; LDHA; Metabolic reprogramming; Succinylation

DOI:  https://doi.org/10.1007/s10565-025-09994-6
Cell Death Discov. 2025 Feb 08. 11(1): 55

Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer.

Liangjian Ma, Wunan Huang, Xiaolei Liang, Hongli Li, Wei Yu, Lexin Liu, Yuelin Guan, Chang Liu, Xiangjun Chen, Lidan Hu.

Endometrial cancer (EC) is a significant health threat to women, with recurrence after treatment posing a major challenge. While abnormal cholesterol metabolism has been implicated in EC progression, the underlying mechanisms remain unclear. In this study, we identified lanosterol synthase (LSS) as a key mediator in cholesterol metabolism associated with EC. We found that LSS is significantly upregulated in EC tissues. Functional assays revealed that LSS promotes cell proliferation and migration, inhibits apoptosis, and drives tumor growth in vivo. Mechanistically, LSS exerts dual effects by accumulating cholesterol esters, thereby enhancing EC cell growth, and activating the MAPK/JNK signaling pathway. Importantly, inhibition of LSS with the specific inhibitor Ro 48-8071 not only reduced EC cell proliferation and suppressed xenograft tumor growth but also inhibited the growth of patient-derived tumor-like cell clusters (PTCs). These findings establish LSS as a novel oncogene in EC, promoting tumor progression through MAPK/JNK signaling activation and cholesterol ester accumulation, and highlight the therapeutic potential of targeting LSS in EC treatment.

DOI: https://doi.org/10.1038/s41420-025-02325-y
Med Oncol. 2025 Feb 10. 42(3): 71

Gefitinib induces apoptosis in Caco-2 cells via ER stress-mediated mitochondrial pathways and the IRE1α/JNK/p38 MAPK signaling axis.

Caiyuan Yu, Jinhui Sun, Xinyi Lai, Zhiming Tan, Yang Wang, Haiyan Du, Zhaobin Pan, Tingyu Chen, Ziping Yang, Shicai Ye, Juanhua Quan, Yu Zhou.

  Gefitinib, a selective EGFR-tyrosine kinase inhibitor, exhibits potent cytotoxic effects on colorectal cancer cells, though its precise mechanisms are not fully understood. In this study, we demonstrated that gefitinib induces a dose-dependent cytotoxic response in Caco-2 cells, characterized by disrupted microtubule networks, impaired migration, and reduced viability. Gefitinib triggered apoptosis, as indicated by increased levels of cleaved caspase-3, PARP, and elevated late apoptosis rates. Mechanistically, gefitinib-induced endoplasmic reticulum (ER) stress, marked by the upregulation of IRE1α, CHOP, and ATF4. ER stress inhibition by 4-PBA significantly reduced apoptosis and restored mitochondrial membrane potential (MMP). Additionally, gefitinib-induced apoptosis was mediated through the mitochondrial pathway, reflected by the modulation of Bcl-2 family proteins, including the upregulation of Bax and Bim. Inhibition of the IRE1α-mediated JNK/p38 MAPK pathway further mitigated gefitinib-induced apoptosis and restored MMP. These findings highlight the critical role of ER stress and the IRE1α-JNK/p38 MAPK axis in gefitinib-induced mitochondrial apoptosis, offering potential therapeutic targets for colorectal cancer.

Keywords:  Apoptosis; Caco-2 cells; Endoplasmic reticulum stress; Gefitinib; MAPK

DOI:  https://doi.org/10.1007/s12032-025-02622-7
Oncol Rep. 2025 Apr;pii: 43. [Epub ahead of print]53(4):

Phillyrin regulates the JAK2/STAT3 signaling pathway by inhibiting TOP2A expression to accelerate ferroptosis in hepatocellular carcinoma.

Ying Zhu, Fenghe Huang, Xiyu Liu, Yunlong Hou, Yong Huang.

  Despite advancements and refinements in the therapeutic approaches for hepatic malignancies, liver cancer remains a prevalent and deadly form of cancer, with its grim outlook posing as a significant clinical challenge. Phillyrin (PHN) has been reported to have anticancer effects, but the anticancer mechanism in liver cancer is ominous. By searching the potential target of PHN in the online database and liver cancer disease database, it was found that there is only one overlap gene, and DNA topoisomerase II alpha (TOP2A) is abnormally expressed in liver cancer tissues. TOP2A overexpression and downregulated hepatocellular carcinoma cell lines were then constructed in vitro, and it was examined whether PHN treatment induced ferroptosis in hepatocellular carcinoma by regulating TOP2A's inhibition of Janus kinase 2/Signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway through phenotypic assay, western blot assay, reverse transcription‑quantitative PCR assay and electron microscopy. The results showed that PHN could inhibit the expression of TOP2A protein and JAK2/STAT3 signaling pathway in hepatoma cells. PHN could also downregulate glutathione peroxidase 4 by suppressing the expression of TOP2A protein. PHN impeded the activity of factor inhibiting hypoxia‑inducible factor 1 alpha, thereby augmenting the synthesis of iron‑dependent apoptosis‑related proteins including cytochrome c oxidase subunit II, long‑chain acyl‑CoA synthetase family member 4 and NADPH oxidase 1, thus facilitating an increase in Fe2+ concentration and accelerating oxidative harm within hepatocellular carcinoma cells, culminating in the induction of ferroptotic cell death in these liver malignancy cells.

Keywords:  JAK2/STAT3 signaling pathway; TOP2A; ferroptosis; hepatocellular carcinoma; phillyrin

DOI:  https://doi.org/10.3892/or.2025.8876
Ann Surg Treat Res. 2025 Feb;108(2): 108-123

Synergistic anticancer effects of mitochondria-targeting peptide combined with paclitaxel in breast cancer cells: a preclinical study.

Juneyoung Ahn, Ok-Hee Kim, Seongeon Jin, Ja-Hyoung Ryu, Dosang Lee, Woo-Chan Park, Say-June Kim.

   Purpose: Mitochondria-accumulating amphiphilic peptide (Mito-FF) was designed to selectively target mitochondria in cancer cells and enhance anticancer effects through its unique structure. Mito-FF consists of (1) diphenylalanine, a β-sheet-forming building block critical for self-assembly; (2) triphenylphosphonium, a mitochondrial targeting moiety guiding the peptide to mitochondria; and (3) pyrene, a fluorescent probe enabling visualization of its accumulation and self-assembly. This study evaluates the anticancer efficacy of Mito-FF in breast cancer cells and explores its combination with paclitaxel, a standard therapy for breast cancer, focusing on its modulation of the epithelial-mesenchymal transition (EMT) pathway.
Methods: In vitro and in vivo experiments were performed using MCF-7 and MDA-MB-231 breast cancer cell lines and their respective xenograft models. Cell viability, migration, EMT marker expression, and apoptosis-related proteins were analyzed.
Results: Mito-FF demonstrated superior inhibition of cell viability and migration compared to paclitaxel alone in both cell lines. Combination therapy with Mito-FF and paclitaxel resulted in enhanced reduction of cell viability and migration. EMT markers were significantly modulated, with decreased mesenchymal markers (Snail and vimentin) and increased epithelial marker (E-cadherin) following combination treatment. Furthermore, the combination therapy synergistically elevated pro-apoptotic markers such as poly (adenosine diphosphate-ribose) polymerase and reduced anti-apoptotic markers such as myeloid cell leukemia 1. In vivo experiments revealed a marked reduction in tumor volume with combination therapy, accompanied by the highest expression levels of E-cadherin and pro-apoptotic marker Bim.
Conclusion: Mito-FF, designed for mitochondrial targeting and visualization, exhibited potent anticancer effects when combined with paclitaxel, in the breast cancer cells.

Keywords:  Breast neoplasms; Epithelial-mesenchymal transition; Mito-FF; Paclitaxel; Triple negative breast neoplasms

DOI:  https://doi.org/10.4174/astr.2025.108.2.108
Mol Cancer Res. 2025 Feb 10.

KSR1 mediates small-cell lung carcinoma tumor initiation and cisplatin resistance.

Deepan Chatterjee, Robert A Svoboda, Dianna H Huisman, Benjamin J Drapkin, Heidi M Vieira, Chaitra Rao, James W Askew, Kurt W Fisher, Robert E Lewis.

Small-cell lung cancer (SCLC) has a dismal five-year survival rate of less than 7%, with limited advances in first line treatment over the past four decades. Tumor-initiating cells (TICs) contribute to resistance and relapse, a major impediment to SCLC treatment. Here, we identify Kinase Suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK signaling cascade, as a critical regulator of SCLC TIC formation and tumor initiation in vivo. We further show that KSR1 mediates cisplatin resistance in SCLC. While 50-70% of control cells show resistance after 6-week exposure to cisplatin, CRISPR/Cas9-mediated KSR1 knockout prevents resistance in >90% of SCLC cells in ASCL1, NeuroD1, and POU2F3 subtypes. KSR1 KO significantly enhances the ability of cisplatin to decrease SCLC TICs via in vitro extreme limiting dilution analysis (ELDA), indicating that KSR1 disruption enhances the cisplatin toxicity of cells responsible for therapeutic resistance and tumor initiation. The ability of KSR1 disruption to prevent cisplatin resistant in H82 tumor xenograft formation supports this conclusion. Previous studies indicate ERK activation inhibits SCLC tumor growth and development. We observe a minimal effect of pharmacological ERK inhibition on cisplatin resistance and no impact on TIC formation via in vitro ELDA. However, mutational analysis of the KSR1 DEF domain, which mediates interaction with ERK, suggests that ERK interaction with KSR1 is essential for KSR1-driven cisplatin resistance. These findings reveal KSR1 as a potential therapeutic target across multiple SCLC subtypes. Implications: Genetic manipulation of KSR1 in SCLC reveals its contribution to cisplatin resistance and tumor initiation.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0652
Adv Sci (Weinh). 2025 Feb 08. e2410058

Nudix Hydrolase 13 Impairs the Initiation of Colorectal Cancer by Inhibiting PKM1 ADP-Ribosylation.

Jinlong Lin, Yixin Yin, Jinghua Cao, Bingxu Zou, Kai Han, Yufan Chen, Siyu Li, Cijun Huang, Jiewei Chen, Yongrui Lv, Shuidan Xu, Dan Xie, Fengwei Wang.

  Metabolic dysregulation has been implicated as a key factor in colorectal cancer (CRC) initiation, however, the underlying driving forces and mechanisms remain poorly understood. Herein, transcriptome profiling of paired early-stage CRCs and adenomas identifies Nudix hydrolase 13 (NUDT13) as a critical suppressor. Elevated NUDT13 expression impedes the proliferation of CRC cells under hypoxic conditions and markedly inhibits CRC initiation by upregulating PKM1. Mechanistically, NUDT13 directly binds and stabilizes PKM1 protein by reducing its poly ADP-ribosylation (PARylation), which is catalyzed by PARP1 at E275/D281/E282/E285/D296, thereby inducing an oxidative phosphorylation (OXPHOS) phenotype in CRC cells. Moreover, spatiotemporal knockout of Nudt13 enhances intestinal tumorigenesis in mice, which can be significantly suppressed by PARP1 inhibitor Olaparib. Notably, residues E245/E248/E249 within the Nudix box motif of NUDT13 are essential for PKM1 PARylation, and a mimic peptide derived from this motif is sufficient to stabilize PKM1 protein and robustly inhibit CRC tumorigenesis. Collectively, this study reveals a previously unknown PARylation-dependent mechanism that regulates PKM1 protein stability and switches the metabolic pathway of CRC cells, providing a promising target for CRC treatment.

Keywords:  ADP‐ribosylation; CRC; NUDT13; PKM1; oxidative phosphorylation; tumor initiation

DOI:  https://doi.org/10.1002/advs.202410058
Adv Sci (Weinh). 2025 Feb 14. e2413121

HDAC2-Mediated METTL3 Delactylation Promotes DNA Damage Repair and Chemotherapy Resistance in Triple-Negative Breast Cancer.

Xiaoniu He, Yuanpei Li, Jian Li, Yu Li, Sijie Chen, Xia Yan, Zhangrong Xie, Jiangfeng Du, Guoan Chen, Jianbo Song, Qi Mei.

  The current treatment of triple-negative breast cancer (TNBC) is still primarily based on platinum-based chemotherapy. However, TNBC cells frequently develop resistance to platinum and experience relapse after drug withdrawal. It is crucial to specifically target and eliminate cisplatin-tolerant cells after platinum administration. Here, it is reported that upregulated N 6-methyladenosine (m6A) modification drives the development of resistance in TNBC cells during cisplatin treatment. Mechanistically, histone deacetylase 2 (HDAC2) mediates delactylation of methyltransferase-like 3 (METTL3), facilitating METTL3 interaction with Wilms'-tumor-1-associated protein and subsequently increasing m6A of transcript-associated DNA damage repair. This ultimately promotes cell survival under cisplatin. Furthermore, pharmacological inhibition of HDAC2 using Tucidinostat can enhance the sensitivity of TNBC cells to cisplatin therapy. This study not only elucidates the biological function of lactylated METTL3 in tumor cells but also highlights its negative regulatory effect on cisplatin resistance. Additionally, it underscores the nonclassical functional mechanism of Tucidinostat as a HDAC inhibitor for improving the efficacy of cisplatin against TNBC.

Keywords:  HDAC2; METTL3; TNBC; chemotherapy resistance; lactylation

DOI:  https://doi.org/10.1002/advs.202413121
Cancer Lett. 2025 Feb 07. pii: S0304-3835(25)00086-2. [Epub ahead of print] 217522

Lactoferrin-Encapsulated Dichloroacetophenone (DAP) nanoparticles enhance drug delivery and anti-tumor efficacy in prostate cancer.

Sugarniya Subramaniam, Varinder Jeet, Jennifer H Gunter, Judith A Clements, Srilakshmi Srinivasan, Amirali Popat, Jyotsna Batra.

  Pyruvate Dehydrogenase Kinase 1 (PDK1) regulates glycolysis and oxidative phosphorylation pathways and is linked to prostate cancer metastasis and poor prognosis. The therapeutic application of 2,2-dichloroacetophenone (DAP), a PDK1 inhibitor, remains underexplored in prostate cancer. In this study we demonstrated that DAP exhibited a superior ability to inhibit prostate cancer cell proliferation, migration and colony formation at a lower concentration (20 μM) compared to a previously established inhibitor, dichloroacetate (DCA), which required concentrations of 30 mM or higher. However, poor aqueous solubility and lower stability of DAP limits its therapeutic application. Nano formulation of DAP with natural lactoferrin enhanced its dispersion and stability by increasing polydispersity index and intensity, and reduced zeta potential values upon conjugation that overcame the solubility limitations of DAP. The lactoferrin-DAP nanoparticles exhibited enhanced therapeutic efficacy by precisely targeting prostate cancer cells that express high lactoferrin receptors and high anti-tumor activity in vitro (at 1 μM) and in mouse prostate tumor xenografts (20 mg/kg). Mechanistically, these nanoparticles induce apoptosis in cancer cells by inducing caspase3/7 activity and disrupting the glycolytic and oxidative phosphorylation pathways. Moreover, lactoferrin-conjugated DAP nanoparticles suppressed the viability of docetaxel-resistant cells exhibiting a higher inhibitory efficacy compared to free DAP and DCA. Targeting PDK1 through lactoferrin-conjugated DAP nanoparticles represents a potent targeted therapeutic strategy for disrupting prostate tumor metabolism and offers promising implications for overcoming drug resistance.

Keywords:  Dichloroacetophenone; Lactoferrin nanoparticles; Metabolism; Prostate cancer; Pyruvate Dehydrogenase Kinase 1

DOI:  https://doi.org/10.1016/j.canlet.2025.217522
Life Sci. 2025 Feb 07. pii: S0024-3205(25)00075-X. [Epub ahead of print]365 123442

DLGAP5 upregulates E2F1 to promote prostate adenocarcinoma neuroendocrine differentiation.

Linghui Liang, Zhiyi Shen, Kaiyu Zhang, Chenglong Zhang, Lai Dong, Rongjie Shi, Lixin Hua, Ruizhe Zhao, Ninghan Feng.

   AIMS: DLGAP5 plays a significant role in promoting cancer progression across various cancers. However, the specific role of DLGAP5 in neuroendocrine differentiation (NED) of prostate cancer (PCa) remains elusive. Our objective is to explore the mechanism by which DLGAP5 mediates NED in PCa.
MATERIALS AND METHODS: Utilizing diverse public databases, we conducted bioinformatics analysis to examine DLGAP5 expression in PCa. We confirmed aberrant DLGAP5 expression in various PCa cell lines through Western blotting. Functional assays both in vivo and in vitro have validated the oncogenic role of DLGAP5 in PCa. Furthermore, we sought to identify downstream key genes to elucidate the mechanisms underlying DLGAP5-mediated NED in PCa. We also identified a small molecule drug, AAPK-25, which specifically targets DLGAP5.
KEY FINDINGS: DLGAP5 was highly expressed in NEPC. The suppression of AR signaling promoted DLGAP5 transcription. DLGAP5 endowed PCa cells with a robust ability to proliferate and migrate. E2F1 was an important downstream target of DLGAP5. DLGAP5 mediated the NED of PCa through E2F1. AAPK-25, as an inhibitor of DLGAP5, inhibited PRAD proliferation by repressing the DLGAP5/E2F1 axis both in vitro and in vivo.
SIGNIFICANCE: We identified the AR/DLGAP5/E2F1 signaling pathway as a pivotal mechanism that facilitates the transition of PCa towards a neuroendocrine phenotype. This pathway may represent a promising therapeutic target for NEPC patients.

Keywords:  ADT resistance; Neuroendocrine differentiation; Prostate cancer

DOI:  https://doi.org/10.1016/j.lfs.2025.123442
Sci Rep. 2025 Feb 12. 15(1): 5149

ZCCHC4 regulates esophageal cancer progression and cisplatin resistance through ROS/c-myc axis.

Lihua Yao, Piao Wu, Fangyi Yao, Bo Huang, Fangmin Zhong, Xiaozhong Wang.

  Zinc finger CCHC-type containing 4 (ZCCHC4) is a newly discovered N6-methyladenosine (m6A) RNA methyltransferase (MTase), which possesses an m6A MTase domain and an RNA-binding protein (RBP) Znf domain. Aberrantly expressed ZCCHC4 has been found to be correlated with poor prognosis and chemoresistance in various tumors, such as hepatocellular carcinoma, lung cancer and colorectal cancer. However, the expression and functional analysis of the role of ZCCHC4 in esophageal cancer (ESCA) is still elusive. The expression of ZCCHC4 in esophageal cancer tissues was evaluated by qPT-PCR and western blot. Serum esophageal tumor markers are detected by electrochemiluminescence immunoassay. Relationship between ZCCHC4 expression and pathway enrichment analysis were analyzed by R. The reactive oxygen species (ROS), cell proliferation, cell cycle and apoptosis of ZCCHC4 in esophageal squamous cell carcinoma (ESCC) cells tested by CCK8 assay and flow cytometry assay. Aberrant expression of ZCCHC4 is associated with cancer stages, lymph node metastasis (LNM), and tumor histology, and poorer Overall Survival (OS) in esophageal cancer. The mRNA level of ZCCHC4 in esophageal cancer patients correlates with serum carcinoembryonic antigen (CEA) levels, Squamous Cell Carcinoma (SCC) markers, and tissue polypeptide antigen (TPA) levels. Knockdown of ZCCHC4 induces DNA damage, leading to an elevation of reactive oxygen species (ROS), which in turn triggers S-phase arrest, enhances apoptosis, augments sensitivity to cisplatin treatment, and inhibits proliferation in esophageal cancer cells. Conversely, overexpression of ZCCHC4 promotes proliferation, inhibits apoptosis, and increases resistance to cisplatin in esophageal cancer cells. Furthermore, scavenging ROS reverses the effects of ZCCHC4 downregulation on both proliferation and apoptosis in esophageal cancer cells. Additionally, downregulation of ZCCHC4 inhibits the progression of esophageal cancer and reduces cisplatin resistance in vivo. In summary, downregulation of ZCCHC4 leads to increased sensitivity of ESCC cells to cisplatin, inhibits proliferation, and promotes apoptosis in esophageal cancer cells, potentially via the ROS/c-myc axis. The study suggests a potential adjunctive role for ZCCHC4 in the diagnosis and treatment of esophageal cancer and aids in further understanding the underlying mechanisms in ESCA progression.

Keywords:  C-myc; Cisplatin resistance; Esophageal cancer; RNA-binding protein; ZCCHC4

DOI:  https://doi.org/10.1038/s41598-025-89628-3
Arch Toxicol. 2025 Feb 13.

SIRT3 regulates PFKFB3-mediated glycolysis to attenuate cisplatin-induced ototoxicity both in vivo and in vitro.

Wei Tang, Shimin Zong, Peiyu Du, Xuan Yu, Ting Li, Bo Liu, Yu Zhong, Wenyang Lei, Wenting Yu, Hongjun Xiao.

  Cochlear hair cell death is the primary cause of cisplatin-induced ototoxicity, currently lacking widely applicable clinical methods for effective prevention and treatment. In this study, an in vivo cisplatin-induced ototoxicity model was established by intraperitoneal injection of 12 mg/kg cisplatin. We found that ablation of SIRT3 exacerbates cisplatin-induced hearing loss and cochlear hair cell damage. An in vitro cisplatin-induced ototoxicity model was established using 5 µM cisplatin in cochlear explants and OC-1 cells. We found that the absence of SIRT3 impairs cochlear hair cell glycolytic metabolism, leading to excessive accumulation of ROS and significant reduction in MMP levels, thereby promoting apoptosis. In contrast, overexpression of SIRT3 in OC-1 cells promotes cochlear hair cell survival and reduces cochlear hair cell apoptosis. Inhibition of PFKFB3 reduces glycolytic metabolism in OC-1 cells, and the protective effect conferred by SIRT3 overexpression is lost. In summary, the protective effect of SIRT3 may be mediated by the regulation of PFKFB3-dependent glycolysis and the mitigation of cisplatin-induced excessive ROS accumulation.

Keywords:  Auditory hair cell; Cisplatin; Glycolysis; PFKFB3; SIRT3; Sensorineural hearing loss

DOI:  https://doi.org/10.1007/s00204-025-03975-8