bims-meract 2024-12-22 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2024–12–22
twenty-six papers selected by
Andrea Morandi, Università degli Studi di Firenze

Exploring Metabolic Approaches for Epithelial Ovarian Cancer Therapy.
Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways.
Theoretical framework and emerging challenges of lipid metabolism in cancer.
LAT4 drives temozolomide induced radiotherapy resistance in glioblastoma by enhancing mTOR pathway activation.
SLC50A1 inhibits the doxorubicin sensitivity in hepatocellular carcinoma cells through regulating the tumor glycolysis.
Metabolic targeting of neuroblastoma, an update.
Redox homeostasis of one-carbon metabolism-dependent reprogramming is critical for RCC progression under exogenous serine/glycine-deprived conditions.
Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells.
Fatty Acid Synthase-Derived Lipid Stores Support Breast Cancer Metastasis.
A hormetic response model for glutamine stress in cancer.
ITGA3 promotes pancreatic cancer progression through HIF1α- and c-Myc-driven glycolysis in a collagen I-dependent autocrine manner.
Targeting PPARγ via SIAH1/2-mediated ubiquitin-proteasomal degradation as a new therapeutic approach in luminal-type bladder cancer.
Identifying the key role of mitochondrial respiration and lipid metabolism in regulating axillary osmidrosis through proteomics analysis.
Calaspargase-Pegol-Mknl Combined with BCL-2 and MCL-1 Inhibition for Acute Myeloid Leukemia.
Microenvironmental G protein-coupled estrogen receptor-mediated glutamine metabolic coupling between cancer-associated fibroblasts and triple-negative breast cancer cells governs tumour progression.
Synergistic enhancement of low-dose radiation therapy via cuproptosis and metabolic reprogramming for radiosensitization in in situ hepatocellular carcinoma.
Enhancing lobaplatin sensitivity in lung adenocarcinoma through inhibiting LDHA-targeted metabolic pathways.
Lipid droplet biogenesis in the ovary.
Kynureninase induce cuproptosis resistance in gastric cancer progression through downregulating lipotic acid synthetase mediated non-canonical mechanism.
Overexpression of PDSS2-Del2 in HCC promotes tumor metastasis by interacting with macrophages.
Metabolic shifts in lipid utilization and reciprocal interactions within the lung metastatic niche of triple-negative breast cancer revealed by spatial multi-omics.
Participation of lipids in the tumor response to photodynamic therapy and its exploitation for therapeutic gain.
P-cadherin mechanoactivates tumor-mesothelium metabolic coupling to promote ovarian cancer metastasis.
Combination of farnesyl-transferase inhibition with KRAS G12D targeting breaks down therapeutic resistance in pancreatic cancer.
Interfering Nuclear Protein Laminb1 Induces DNA Damage and Reduces Vemurafenib Resistance in Melanoma Cells In Vitro.
Mitochondrial-targeting strategies with homoharringtonine: A novel approach for chemoresistant rectal cancer.

J Cell Physiol. 2024 Dec 15. e31495

Exploring Metabolic Approaches for Epithelial Ovarian Cancer Therapy.

Sangeeta Kumari, Shraddha Gupta, Aisha Jamil, Deyana Tabatabaei, Sergey Karakashev.

Epithelial ovarian cancer (EOC) has the highest mortality rate among malignant tumors of the female reproductive system and the lowest survival rate. This poor prognosis is due to the aggressive nature of EOC, its late-stage diagnosis, and the tumor's ability to adapt to stressors through metabolic reprogramming. EOC cells sustain their rapid proliferation by altering the uptake, utilization, and regulation of carbohydrates, lipids, and amino acids. These metabolic changes support tumor growth and contribute to metastasis, chemotherapy resistance, and immune evasion. Targeting these metabolic vulnerabilities has shown promise in preclinical studies, with some therapies advancing to clinical trials. However, challenges remain due to tumor heterogeneity, adaptive resistance mechanisms, and the influence of the tumor microenvironment. This review provides a comprehensive summary of metabolic targets for EOC treatment and offers an overview of the current landscape of clinical trials focusing on ovarian cancer metabolism. Future efforts should prioritize combination therapies that integrate metabolic inhibitors with immunotherapies or chemotherapy. Advances in precision medicine and multi-omics approaches will be crucial for identifying patient-specific metabolic dependencies and improving outcomes. By addressing these challenges, metabolism-based therapies can significantly transform the treatment of this devastating disease.

DOI: https://doi.org/10.1002/jcp.31495
Cell Commun Signal. 2024 Dec 18. 22(1): 597

Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways.

Debojyoty Bandyopadhyay, Ellen T Tran, Ruchi A Patel, Matthew A Luetzen, Kevin Cho, Leah P Shriver, Gary J Patti, Mark A Varvares, David A Ford, Kyle S McCommis, Ratna B Ray.

  One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.

Keywords:  Autophagy; Glycolysis; Head and neck cancer; Lipid metabolism; Metabolites; Momordicine-I

DOI:  https://doi.org/10.1186/s12964-024-01951-w
Semin Cancer Biol. 2024 Dec 12. pii: S1044-579X(24)00096-8. [Epub ahead of print]108 48-70

Theoretical framework and emerging challenges of lipid metabolism in cancer.

Qiuying Gu, Yuan Wang, Ping Yi, Chunming Cheng.

  Elevated lipid metabolism is one of hallmarks of malignant tumors. Lipids not only serve as essential structural components of biological membranes but also provide energy and substrates for the proliferation of cancer cells and tumor growth. Cancer cells meet their lipid needs by coordinating the processes of lipid absorption, synthesis, transport, storage, and catabolism. As research in this area continues to deepen, numerous new discoveries have emerged, making it crucial for scientists to stay informed about the developments of cancer lipid metabolism. In this review, we first discuss relevant concepts and theories or assumptions that help us understand the lipid metabolism and -based cancer therapies. We then systematically summarize the latest advancements in lipid metabolism including new mechanisms, novel targets, and up-to-date pre-clinical and clinical investigations of anti-cancer treatment with lipid metabolism targeted drugs. Finally, we emphasize emerging research directions and therapeutic strategies, and discuss future prospective and emerging challenges. This review aims to provide the latest insights and guidance for research in the field of cancer lipid metabolism.

Keywords:  Cancer; Cancer therapy; Cancer treatment; Cholesterol; Fatty acids; Inhibitors; Lipid metabolism; Lipid synthesis; Theoretical framework; Tumor metabolism

DOI:  https://doi.org/10.1016/j.semcancer.2024.12.002
Cancer Cell Int. 2024 Dec 18. 24(1): 407

LAT4 drives temozolomide induced radiotherapy resistance in glioblastoma by enhancing mTOR pathway activation.

Wenrui Zang, Yangwu Liu, Jiajun Zheng, Yifeng Huang, Lei Chen, Chiyang Li, Jiakun Zhao, Qiang Zhou, Yangheng Xu, Zhenyuan Wang, Yongfu Cao, Wanling Zhang, Junjie Li, Yuntao Lu.

   BACKGROUND: Glioblastoma multiforme (GBM) represents the most prevalent form of primary malignant tumor within the central nervous system. The emergence of resistance to radiotherapy and chemotherapy represents a significant impediment to advancements in glioma treatment.
METHODS: We established temozolomide (TMZ)-resistant GBM cell lines by chronically exposing U87MG cell lines to TMZ, and dimethyl sulfoxide (DMSO) was used as placebo control. In vivo and in vitro experiments verified the resistance of resistant cells to chemotherapy and radiotherapy. LAT4 was identified by transcriptomics to be associated with GBM treatment resistance and relapse. The relationship between LAT4 and mTOR pathway activity was also analyzed. Finally, the effect of BCH (LAT inhibitor) combined with radiotherapy on GBM prognosis was verified in vivo.
RESULTS: We have first confirmed that TMZ not only induces resistance to chemotherapy in GBM cells but also enhances their resistance to radiotherapy, which is a significant finding in the process of building TMZ-resistant U87MG GBM cell lines. We then performed comprehensive transcriptomic analysis and identified amino acid metabolism as a potential key factor in radiotherapy resistance. Specifically, we confirmed that the upregulation of LAT4 following chemotherapy enhances leucine metabolism within tumors in vitro and in vivo, thereby modulating the mechanistic target of mTOR pathway and leading to radiotherapy resistance. Of note, the application of inhibitors targeting leucine metabolism was shown to restore the sensitivity of these cells to radiotherapy, highlighting a potential therapeutic strategy for overcoming resistance in GBM.
CONCLUSIONS: Our study links tumor sensitivity to chemotherapy and radiotherapy and highlights the critical role of LAT4 in activating the mTOR pathway and GBM radiotherapy resistance. It suggests ways to improve radiotherapy sensitivity to GBM.

Keywords:  Amino acid metabolism; GBM; LAT4; Radiotherapy; TMZ; mTOR pathway

DOI:  https://doi.org/10.1186/s12935-024-03590-0
Cell Death Discov. 2024 Dec 18. 10(1): 495

SLC50A1 inhibits the doxorubicin sensitivity in hepatocellular carcinoma cells through regulating the tumor glycolysis.

Ganggang Wang, Wenzhi Jin, Lianmei Zhang, Meiyuan Dong, Xin Zhang, Zhijie Zhou, Xiaoliang Wang.

Metabolic reprogramming has been found to be closely associated with the occurrence and development of hepatocellular carcinoma (HCC). The relationship between SLC50A1, a member of the SLC family involved in glucose transmembrane transport, and HCC remains unclear. This study aims to investigate the function and underlying mechanisms of SLC50A1 in the occurrence and progression of HCC. Based on bioinformatics analysis and clinical sample testing, we observed a significant upregulation of SLC50A1 in HCC, which is correlated with unfavorable prognosis in HCC patients. Additionally, there is a noticeable correlation between the expressions of SLC50A1 and METTL3. Further in vitro and in vivo experiments confirmed that SLC50A1 can regulate cellular glycolysis and the cell cycle, thereby promoting the proliferation of HCC cells while reducing apoptosis. Moreover, our findings indicate that SLC50A1 enhances resistance of HCC cells to DOX and 2-DG. Furthermore, we discovered that the m6A methyltransferase METTL3 mediates the methylation modification of SLC50A1. The recognition and binding of the modified SLC50A1 by IGF2BP2 subsequently promote its stability and translational expression. Consequently, our research identifies the METTL3/SLC50A1 axis as a novel therapeutic target in the context of HCC.

DOI: https://doi.org/10.1038/s41420-024-02261-3
Cancer Lett. 2024 Dec 14. pii: S0304-3835(24)00788-2. [Epub ahead of print] 217393

Metabolic targeting of neuroblastoma, an update.

Leila Jahangiri.

  Neuroblastoma is a paediatric cancer of the sympathetic nervous system that originates from the neural crest and can be categorised into stages and risk groups. Risk groups inform treatment options and high-risk cases bear a 50% probability of relapse post-treatment remission. In neuroblastoma, MYCN amplification is the strongest predictor of unfavourable patient prognosis; circa 50% of high-risk cases display MYCN amplification. This dismal prognosis is perhaps influenced by the MYCN-driven metabolic rewiring of these cells since the MYC family is indicated in the regulation of proliferation, cell death, metabolism, differentiation, and protein synthesis. This review aims to capture the most recent studies that investigate metabolic rewiring in MYCN-amplified and MYCN-activated cells from the perspective of alterations to glycolysis, the TCA cycle, and oxidative phosphorylation, in addition to changes to amino acid, nucleotide, and lipid metabolism that can be relevant to therapy. A better understanding of the metabolic profile of MYCN-amplified disease will facilitate the identification of effective treatment options and improve the prognosis of high-risk neuroblastoma patients.

Keywords:  MYCN amplification; Neuroblastoma; metabolism; therapy

DOI:  https://doi.org/10.1016/j.canlet.2024.217393
BMC Cancer. 2024 Dec 18. 24(1): 1515

Redox homeostasis of one-carbon metabolism-dependent reprogramming is critical for RCC progression under exogenous serine/glycine-deprived conditions.

Huijuan Wang, Mengzhen Fan, Sichang Liu, Mengjiao Qu, Xin Hou, Junqing Hou, Yanxin Xu, Xiaodi Shang, Chen Liu, Mingxia He, Jianzheng Gao, Jingying Chen, Xia Li.

   BACKGROUND: Serine/glycine are critical for the growth and survival of cancer cells. Some cancer cells are more dependent on exogenous serine/glycine than endogenously synthesized serine/glycine. However, the function and underlying mechanisms of exogenous serine/glycine in renal cell carcinoma (RCC) remain unclear.
METHODS: We conducted a comprehensive assessment of RCC progression under conditions of exogenous serine/glycine deprivation and explored the underlying mechanism via immunofluorescence, autophagic flux analysis, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) measurements.
RESULTS: The expression of the serine synthesis pathway enzymes was decreased in RCC specimens, the de novo serine synthesis pathway (SSP) was reduced in RCC. And the levels of endogenously synthesized serine/glycine were little. Yet, the exogenous serine/glycine deprivation significantly inhibited the growth of RCC cells both in vitro and in vivo, indicating that exogenous serine/glycine were important for RCC progression. Mechanistically, the deprivation of exogenous serine/glycine disrupted one-carbon metabolism and increased the ratio of NAD(P)+/NAD(P)H, resulting in the accumulation of reactive oxygen species (ROS) and oxidative stress, which induced autophagic flux and enhanced lysosome membrane permeabilization (LMP), leading to the release of lysosomal cathepsins into the cytoplasm, which ultimately triggered lysosomal dependent cell death (LDCD) and inhibited the progression of RCC.
CONCLUSIONS: Our results indicate that exogenous serine/glycine are critical for RCC progression by maintaining one-carbon metabolism-dependent redox homeostasis, which provides new insights for the development of dietary serine/glycine starvation-based therapeutic approaches for RCC.

Keywords:  Lysosomal dependent cell death; Lysosome membrane permeabilization; ROS; Renal cell carcinoma; Serine/glycine

DOI:  https://doi.org/10.1186/s12885-024-13304-4
Cell Death Dis. 2024 Dec 18. 15(12): 902

Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells.

Justin Kim, Bryce Brunetti, Ayanesh Kumar, Ankit Mangla, Kord Honda, Akihiro Yoshida.

The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.

DOI: https://doi.org/10.1038/s41419-024-07284-3
Res Sq. 2024 Dec 05. pii: rs.3.rs-5510550. [Epub ahead of print]

Fatty Acid Synthase-Derived Lipid Stores Support Breast Cancer Metastasis.

Chaylen Andolino, Eylem Kulkoyluoglu Cotul, Zilin Xianyu, Yun Li, Divya Bhat, Mitchell Ayers, Kimberly K Buhman, Stephen D Hursting, Michael K Wendt, Dorothy Teegarden.

Lipid accumulation is associated with breast cancer metastasis. However, the mechanisms underlying how breast cancer cells increase lipid stores and their functional role in disease progression remain incompletely understood. Herein we quantified changes in lipid metabolism and characterized cytoplasmic lipid droplets in metastatic versus non-metastatic breast cancer cells. 14 C-labeled palmitate was used to determine differences in fatty acid (FA) uptake and oxidation. Despite similar levels of palmitate uptake, metastatic cells increase lipid accumulation and oxidation of endogenous FAs compared to non-metastatic cells. Isotope tracing also demonstrated that metastatic cells support increased de novo lipogenesis by converting higher levels of glutamine and glucose into the FA precursor, citrate. Consistent with this, metastatic cells displayed increased levels of fatty acid synthase (FASN) and de novo lipogenesis. Genetic depletion or pharmacologic inhibition of FASN reduced cell migration, survival in anoikis assays, and in vivo metastasis. Finally, global proteomic analysis indicated that proteins involved in proteasome function, mitotic cell cycle, and intracellular protein transport were reduced following FASN inhibition of metastatic cells. Overall, these studies demonstrate that breast cancer metastases accumulate FAs by increasing de novo lipogenesis, storing TAG as cytoplasmic lipid droplets, and catabolizing these stores to drive several FAO-dependent steps in metastasis.

DOI: https://doi.org/10.21203/rs.3.rs-5510550/v1
Trends Cancer. 2024 Dec 16. pii: S2405-8033(24)00274-7. [Epub ahead of print]

A hormetic response model for glutamine stress in cancer.

Shea F Grenier, Cosimo Commisso.

  Glutamine metabolism supports the development and progression of many cancers and is considered a therapeutic target. Attempts to inhibit glutamine metabolism have resulted in limited success and have not translated into clinical benefit. The outcomes of these clinical studies, along with preclinical investigations, suggest that cellular stress responses to glutamine deprivation or targeting may be modeled as a biphasic hormetic response. By recognizing the multifaceted aspects of glutamine metabolism inhibition within a more comprehensive biological framework, the adoption of this model may guide future fundamental and translational studies. To achieve clinical efficacy, we posit that as a field we will need to anticipate the hormetic effects of glutamine stress and consider how best to co-target cancer cell adaptive mechanisms.

Keywords:  cancer; glutamine stress; hormesis; metabolism; targeted therapies; therapeutics

DOI:  https://doi.org/10.1016/j.trecan.2024.11.008
Cancer Gene Ther. 2024 Dec 17.

ITGA3 promotes pancreatic cancer progression through HIF1α- and c-Myc-driven glycolysis in a collagen I-dependent autocrine manner.

Rongkun Li, Qian Ji, Shengqiao Fu, Jichun Gu, Dejun Liu, Lu Wang, Xiao Yuan, Yi Wen, Chunhua Dai, Hengchao Li.

Pancreatic cancer is characterized by severe metabolic stress due to its prominent desmoplasia and poor vascularization. Integrin subunit alpha 3 (ITGA3) is a cell surface adhesion protein involved in tumor progression. However, the role of ITGA3 in pancreatic cancer progression, especially in metabolic reprogramming, remains largely unknown. In this study, we found that ITGA3 expression is elevated in pancreatic cancer tissues and predicts poor prognosis for patients with pancreatic cancer. Functional assays revealed that ITGA3 promotes the growth and liver metastasis of pancreatic cancer via boosting glycolysis. Mechanistically, Collagen I (Col1) derived from cancer cells acts as a ligand for ITGA3 to activate the FAK/PI3K/AKT/mTOR signaling pathway in an autocrine manner, thereby increasing the expression of HIF1α and c-Myc, two critical regulators of glycolysis. Blockade of Col1 by siRNA or of ITGA3 by a blocking antibody leads to specific inactivation of the FAK/PI3K/AKT/mTOR pathway and impairs malignant tumor behaviors induced by ITGA3. Thus, our data indicate that ITGA3 enhances glycolysis to promote pancreatic cancer growth and metastasis via increasing HIF1α and c-Myc expression in a Col1-dependent autocrine manner, making ITGA3 as a candidate diagnostic biomarker and a potential therapeutic target for pancreatic cancer.

DOI: https://doi.org/10.1038/s41417-024-00864-7
Cell Death Dis. 2024 Dec 18. 15(12): 908

Targeting PPARγ via SIAH1/2-mediated ubiquitin-proteasomal degradation as a new therapeutic approach in luminal-type bladder cancer.

Chih-Chieh Tu, Tsung-Han Hsieh, Cheng-Ying Chu, Yu-Chen Lin, Bo-Jyun Lin, Chun-Han Chen.

Bladder cancer (BC) is the second most prevalent genitourinary malignancy worldwide. Despite recent approvals of immune checkpoint inhibitors and targeted therapy for muscle invasive or recurrent BC, options remain limited for patients with non-muscle invasive BC (NMIBC) refractory to Bacillus Calmette-Guérin (BCG) and chemotherapy. NMIBC is more frequently classified as a luminal subtype, in which increased PPARγ activity is a key feature in promoting tumor growth and evasion of immunosurveillance. Cinobufotalin is one of the major compound of bufadienolides, the primary active components of toad venom that has been utilized in the clinical treatment of cancer. We herein focused on cinobufotalin, examining its anticancer activity and molecular mechanisms in luminal-type NMIBC. Our results newly reveal that cinobufotalin strongly suppresses the viability and proliferation of luminal BC cells with minimal cytotoxic effects on normal uroepithelial cells, and exhibits significant antitumor activity in a RT112 xenograft BC model. Mechanistically, our sub-G1-phase cell accumulation, Annexin V staining, caspase-3/8/9 activation, and PARP activation analyses show that cinobufotalin induces apoptosis in luminal-type BC cells. Cinobufotalin significantly inhibited the levels of PPARγ and its downstream targets, as well as lipid droplet formation and free fatty acid levels in RT112 cells. PPARγ overexpression rescued RT112 cells from cinobufotalin-induced apoptosis and mitigated the downregulation of FASN and PLIN4. Finally, we show seemingly for the first time that cinobufotalin promotes SIAH1/2-mediated proteasomal degradation of PPARγ in luminal BC cells. Together, these findings compellingly support the idea that cinobufotalin could be developed as a promising therapeutic agent for treating luminal-type NMIBC.

DOI: https://doi.org/10.1038/s41419-024-07298-x
Arch Dermatol Res. 2024 Dec 14. 317(1): 128

Identifying the key role of mitochondrial respiration and lipid metabolism in regulating axillary osmidrosis through proteomics analysis.

Qiong Gao, Yuxin Liu, Jihui Huang, Lipeng Wang.

  Axillary osmidrosis (AO) affects a large number of young people in Asia, resulting from a combination of body and bacterial metabolism. This study aimed to explore the pathogenesis of AO through proteomics. Apocrine gland tissues from 3 mild and 3 severe AO patients were analyzed using 4D label-free proteomics, followed by bioinformatics analysis. The RNA and protein levels of the predicted key regulators were further validated by qPCR and immunohistochemistry in additional AO tissues. A total of 5066 proteins were identified, of which 323 were significantly upregulated and 412 were downregulated (by |log2FC|> 1 and p < 0.05). GO terms related to mitochondria, oxidation-reduction processes, and peroxisomes were significantly enriched among the upregulated DEPs, suggesting enhanced energy metabolism in severe AO patients. Downregulated DEPs were enriched in ribosome, phagosome, and platelet activation pathways according to KEGG, while upregulated DEPs were significantly enriched in metabolic pathways, valine, leucine, and isoleucine degradation, peroxisomes, and fatty acid degradation. The enriched pathways suggest that apocrine gland tissues develop AO by increasing blood flow to promote sweating and secreting excessive short-chain fatty acids by coupling mitochondrial respiration with incomplete metabolism of lipids and branched-chain amino acids. This metabolic coupling may have implications for studies on cardiovascular disease, metabolic disorders, and oxidative stress. Key proteins in the signaling network were further confirmed by qPCR and immunohistochemistry, including reduced FGA and ITGA2B, and increased EHHADH and ACOX1. Our proteomics analysis suggests a paradigm of lipid metabolism involving mitochondrial respiration and incomplete lipid and branched-chain amino acid metabolism as the pathogenesis of AO. We also suggest that EHHADH is a key regulator in promoting AO in this process.

Keywords:  Axillary osmidrosis; Bromhidrosis; Clinical samples; EHHADH, Lipid metabolism; Mitochondrion

DOI:  https://doi.org/10.1007/s00403-024-03616-7
Int J Mol Sci. 2024 Dec 05. pii: 13091. [Epub ahead of print]25(23):

Calaspargase-Pegol-Mknl Combined with BCL-2 and MCL-1 Inhibition for Acute Myeloid Leukemia.

Dominique Bollino, Xinrong Ma, Kayla M Tighe, Andrea Casildo, Katharina Richard, Antonino Passaniti, Brandon Carter-Cooper, Erin T Strovel, Ashkan Emadi.

  Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA). We report that CalPegA enhances the anti-leukemic effect of S55746 but does not impact the activity of S63845. The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML.

Keywords:  BCL-2; MCL-1; acute myeloid leukemia; asparaginase

DOI:  https://doi.org/10.3390/ijms252313091
Clin Transl Med. 2024 Dec;14(12): e70131

Microenvironmental G protein-coupled estrogen receptor-mediated glutamine metabolic coupling between cancer-associated fibroblasts and triple-negative breast cancer cells governs tumour progression.

Chongwu He, Meixi Peng, Xiaoqiang Zeng, Hanzhi Dong, Zhengkui Sun, Jiawei Xu, Manran Liu, Liyan Liu, Yanxiao Huang, Zhiqiang Peng, Yu-An Qiu, Chunling Jiang, Bin Xu, Tenghua Yu.

   BACKGROUND: Triple-negative breast cancer (TNBC) is a particularly aggressive type of breast cancer, known for its lack of effective treatments and unfavorable prognosis. The G protein-coupled estrogen receptor (GPER), a novel estrogen receptor, is linked to increased malignancy in various cancers. However, its involvement in the metabolic regulation of cancer-associated fibroblasts (CAFs), a key component in the tumour microenvironment, remains largely unexplored. This study investigates how GPER influences the metabolic interaction between CAFs and TNBC cells, aiming to identify potential therapeutic targets.
METHODS: The co-culture system is performed to examine the interaction between CAFs and TNBC cells, with a focus on GPER-mediated glutamine production and release by CAFs and its subsequent uptake and utilization by TNBC cells. The definite roles of microenvironmental GPER/cAMP/PKA/CREB signalling in regulating the expression of glutamine synthetase (GLUL) and lactate dehydrogenase B (LDHB) are further investigated.
RESULTS: Our findings reveal that estrogen-activated GPER in CAFs significantly upregulates the expression of GLUL and LDHB, leading to increased glutamine production. This glutamine is then secreted into the extracellular matrix and absorbed by TNBC cells, enhancing their viability, motility, and chemoresistance both in vitro and in vivo. TNBC cells further metabolize the glutamine through the glutamine transporter (ASCT2) and glutaminase (GLS1) axes, which, in turn, promote mitochondrial activity and tumour progression.
CONCLUSIONS: The study identifies GPER as a critical mediator of metabolic coupling between CAFs and TNBC cells, primarily through glutamine metabolism. Targeting the estrogen/GPER/glutamine signalling axis in CAFs offers a promising therapeutic strategy to inhibit TNBC progression and improve patient outcomes. This novel insight into the tumour microenvironment highlights the potential of metabolic interventions in treating TNBC.
KEY POINTS: Estrogen-activated GPER in CAFs enhances GLUL and LDHB expression via the cAMP/PKA/CREB signalling, facilitating glutamine production and utilization. Microenvironmental GPER-induced glutamine serves as a crucial mediator of metabolic coupling between CAFs and TNBC cells, boosting tumour progression by enhancing mitochondrial function. Targeting the glutamine metabolic coupling triggered by estrogen/GPER/GLUL signalling in CAFs is a promising therapeutic strategy for TNBC treatment.

Keywords:  CAFs; GPER; TNBC; glutamine metabolism; tumour progression

DOI:  https://doi.org/10.1002/ctm2.70131
J Nanobiotechnology. 2024 Dec 19. 22(1): 772

Synergistic enhancement of low-dose radiation therapy via cuproptosis and metabolic reprogramming for radiosensitization in in situ hepatocellular carcinoma.

Ni Shao, Yongqing Yang, Genwen Hu, Qiao Luo, Nianlan Cheng, Jifeng Chen, Yanyu Huang, Hong Zhang, Liangping Luo, Zeyu Xiao.

   BACKGROUND: Radiotherapy (RT) is a primary clinical approach for cancer treatment, but its efficacy is often hindered by various challenges, especially radiation resistance, which greatly compromises the therapeutic effectiveness of RT. Mitochondria, central to cellular energy metabolism and regulation of cell death, play a critical role in mechanisms of radioresistance. In this context, cuproptosis, a novel copper-induced mitochondria-respiratory-dependent cell death pathway, offers a promising avenue for radiosensitization.
RESULTS: In this study, an innovative theranostic nanoplatform was designed to induce cuproptosis in synergy with low-dose radiation therapy (LDRT, i.e., 0.5-2 Gy) for the treatment of in situ hepatocellular carcinoma (HCC). This approach aims to reverse the hypoxic tumor microenvironment, promoting a shift in cellular metabolism from glycolysis to oxidative phosphorylation (OXPHOS), thereby enhancing sensitivity to cuproptosis. Concurrently, the Fenton-like reaction ensures a sustained supply of copper and depletion of glutathione (GSH), inducing cuproptosis, disrupting mitochondrial function, and interrupting the energy supply. This strategy effectively overcomes radioresistance and enhances the therapeutic efficacy against tumors.
CONCLUSIONS: In conclusion, this study elucidates the intricate interactions among tumor hypoxia reversal, cuproptosis, metabolic reprogramming, and radiosensitization, particularly in the context of treating in situ hepatocellular carcinoma, thereby providing a novel paradigm for radiotherapy.

Keywords:  Cuproptosis; Low-dose radiation therapy; Metabolic reprogramming; Mitochondria; Radiosensitization

DOI:  https://doi.org/10.1186/s12951-024-03011-4
PLoS One. 2024 ;19(12): e0310825

Enhancing lobaplatin sensitivity in lung adenocarcinoma through inhibiting LDHA-targeted metabolic pathways.

Siyu Yuan, Wenjie Ou, Xuguang Mi, Junjie Hou.

BACKGROUND AND OBJECTIVE: Lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), is associated with high incidence and mortality rates. Effective treatment options are limited due to the frequent development of multidrug resistance, making it crucial to identify new therapeutic targets and sensitizing agents. This study investigates the role of Lactate dehydrogenase A (LDHA) in enhancing the chemotherapy sensitivity of Lobaplatin (LBP) in LUAD.
METHODS: Bioinformatics analyses were performed using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to assess LDHA expression in LUAD tissues. LUAD cell lines A549 and NCL-H1975 were treated with siRNA targeting LDHA and the small molecule inhibitor Oxamate. We measured changes in lactate production, ATP levels, NAD+ and pyruvate levels, and assessed cell viability. The chemotherapy sensitivity to Lobaplatin was evaluated, and key signaling pathways related to chemotherapy resistance were analyzed.
RESULTS: The inhibition of LDHA resulted in a significant reduction in lactate production and ATP levels, along with an increase in NAD+ and pyruvate levels. These metabolic alterations led to decreased cell viability and enhanced sensitivity to Lobaplatin. The study identified the PI3K/AKT signaling pathway as a critical mediator of this enhanced sensitivity, with reduced phosphorylation of AKT observed upon LDHA inhibition. Furthermore, the combination of LDHA inhibition and Lobaplatin treatment demonstrated a synergistic effect, significantly inhibiting tumor growth and highlighting the potential of LDHA as a therapeutic target to overcome drug resistance in LUAD.
CONCLUSION: Targeting LDHA and disrupting lactate metabolism and its signaling pathways can effectively enhance the sensitivity of LUAD to Lobaplatin, providing a promising approach to overcoming multidrug resistance. These findings offer valuable insights into developing new treatment strategies for lung adenocarcinoma, emphasizing the role of metabolic pathways in cancer therapy.

DOI: https://doi.org/10.1371/journal.pone.0310825
Reprod Med Biol. 2024 Jan-Dec;23(1):23(1): e12618

Lipid droplet biogenesis in the ovary.

Megumi Ibayashi, Satoshi Tsukamoto.

   Background: Lipid droplets (LDs) are organelles consisting of a central core of neutral lipids covered by a single layer of phospholipids and are found in most eukaryotic cells. Accumulating evidence suggests that LDs not only store neutral lipids but also coordinate with other organelles for lipid metabolism within cells.
Methods: This review focuses on the synthesis of LDs during follicular development and highlights the factors involved in the regulation of LD biogenesis within the ovary.
Main Findings: In the mammalian ovary, the presence of LDs has long been recognized mainly by morphological analysis. However, their distribution in the ovary varies according to the region and cell type; for example, LDs are abundant in the medulla, which has a rich blood vessel network, in interstitial cells, which are the site of steroid production, and surrounding growing follicles, while they are poor in granulosa cells within follicles. LDs are also enriched in the corpus luteum after ovulation and massively accumulate in atretic follicles during follicular growth. Furthermore, LD synthesis is synchronized with angiogenesis during follicular development.
Conclusion: Addressing the functional link between LD biogenesis and angiogenesis is essential for understanding the molecular basis underlying LD biology, as well as the ovarian dysfunction with metabolic disorders.

Keywords:  angiogenesis; follicle; lipid droplet; mouse; ovary

DOI:  https://doi.org/10.1002/rmb2.12618
Cell Signal. 2024 Dec 14. pii: S0898-6568(24)00540-0. [Epub ahead of print]127 111565

Kynureninase induce cuproptosis resistance in gastric cancer progression through downregulating lipotic acid synthetase mediated non-canonical mechanism.

Yuanda Liu, Changfeng Li, Xilun Cui, Chang Liu, Pengtuo Xiao, Wei Yang.

   BACKGROUND: Gastric cancer (GC) is among the most malignant tumors, with the lowest five-year survival rate, and limited treatment options. Kynureninase (KYNU), is a key molecule in tryptophan metabolism and promotes tumor progression and immunosuppression. Cuproptosis is a non-apoptotic cell death mechanism, primarily due to oxidative stress caused by copper ion accumulation, that is related to tumor progression and drug resistance. KYNU can inhibit ferroptosis of tumor cells by alleviating oxidative stress. Here, we explored whether KYNU can regulate the biological behavior of GC and cuproptosis.
METHODS: Expression, prognostic association, and functional analysis of KYNU in GC and tumor-adjacent tissues were analyzed using data from The Cancer Genome Atlas and clinical specimens. Effects of KYNU on proliferation, invasion, metastasis, and cuproptosis of GC cells were detected by CCK8, clone formation, Transwell, and flow cytometry assays. Elesclomol (ES) combined with CuCl2 were used to induce cuproptosis in GC cells. 3-hydroxyanthranilic acid (3-HA) was used to indicate KYNU function. Key cuproptosis genes were detected by qPCR and WB. The effects of KYNU on GC cell behavior and cuproptosis through lipoic acid synthetase (LIAS) were verified by stable overexpression and knockdown of LIAS.
RESULTS: KYNU is highly expressed in GC, and high KYNU expression is an independent predictor of poor prognosis in patients with GC. KYNU can promote GC cell proliferation, invasion, metastasis, and cuproptosis resistance. 3-HA had a certain inhibitory effect on the expression of LIAS, but it was not significant. KYNU had no effect on the intracellular 3-HA level. KYNU expression was negatively correlated with that of LIAS, and promoted GC cell proliferation, invasion, metastasis, and cuproptosis resistance by downregulating LIAS.
CONCLUSIONS: KYNU can promote GC proliferation, invasion, metastasis, and cuproptosis resistance.This effect is not associated with its metabolite 3-HA, but is achieved by a non classical mechanisms that downregulating the expression of LIAS, a key gene of cuproptosis.

Keywords:  Cuproptosis; Gastric Cancer; KYNU; LIAS; Tryptophan metabolism

DOI:  https://doi.org/10.1016/j.cellsig.2024.111565
Cell Death Discov. 2024 Dec 18. 10(1): 506

Overexpression of PDSS2-Del2 in HCC promotes tumor metastasis by interacting with macrophages.

Guanghui Li, Daqin Suo, Yuanzhen Ma, Tingting Zeng, Jiarong Zhan, Yunfei Yuan, Xin-Yuan Guan, Yan Li.

Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide. According to the Global Cancer Statistics 2020, liver cancer remains the third cause of cancer death globally. Despite significant advances in systemic therapy, HCC still has one of the worst prognoses due to its frequent recurrence and metastasis. Previously we found that PDSS2-Del2 (prenyl diphosphate synthase subunit 2 with exon 2 deletion), a novel variant of PDSS2, could promote HCC metastasis and angiogenesis via activating NF-κB. In this study, we elucidate a novel mechanism by which PDSS2-Del2 enhances HCC metastasis. The overexpression of PDSS2-Del2 in HCC cells promotes the ubiquitination and degradation of SKOR1, consequently heightening SMAD3 phosphorylation. Subsequently, the expression and secretion of MST1 (macrophage stimulatory protein 1) are upregulated, resulting in enhanced recruitment of macrophages into tumor tissues where they differentiate into M2-type macrophages. Co-culture with PDSS2-Del2 overexpressed HCC cells activated the PI3K/AKT signaling pathway in macrophages, and more MMP2 and MMP9 were secreted, which facilitated HCC cell dissemination. Our study elucidates a novel molecular mechanism by which PDSS2-Del2 promotes HCC metastasis, which may contribute to the development of effective HCC clinical treatment and prevent tumor metastasis. Furthermore, MST1 could be a potential therapeutic target, and MST1 inhibitors might be integrated into clinical practice for HCC patients with high expression of PDSS2-Del2.

DOI: https://doi.org/10.1038/s41420-024-02274-y
Cell Death Dis. 2024 Dec 18. 15(12): 899

Metabolic shifts in lipid utilization and reciprocal interactions within the lung metastatic niche of triple-negative breast cancer revealed by spatial multi-omics.

Jung-Yu Kan, Hsiao-Chen Lee, Ming-Feng Hou, Hung-Pei Tsai, Shu-Fang Jian, Chao-Yuan Chang, Pei-Hsun Tsai, Yi-Shiuan Lin, Ying-Ming Tsai, Kuan-Li Wu, Yung-Chi Huang, Ya-Ling Hsu.

The Triple-Negative Breast Cancer (TNBC) subtype constitutes 15-20% of breast cancer cases and is associated with the poorest clinical outcomes. Distant metastasis, particularly to the lungs, is a major contributor to the high mortality rates in breast cancer patients. Despite this, there has been a lack of comprehensive insights into the heterogeneity of metastatic tumors and their surrounding ecosystem in the lungs. In this study, we utilized spatial RNA sequencing technology to investigate the heterogeneity of lung metastatic tumors and their microenvironment in two spontaneous lung metastatic mouse models. Our findings revealed an increase in metabolic-related genes within the cancer cells, with the hub gene Dlat (Dihydrolipoamide S-Acetyltransferase) showing a significant association with the development of lung metastatic tumors. Upregulation of Dlat led to the reprogramming of fatty acid utilization, markedly enhancing the bioenergetic capacity of cancer cells. This finding was corroborated by the increased dependence on fatty acid utilization in lung metastatic cancer cells, and inhibition of Dlat in breast cancer cells exhibited a reduced oxygen consumption rate. Consequently, inhibition of Dlat resulted in decreased survival capacity of breast cancer by reducing cancer stem cell properties and cell adhesion in the lung in vivo. The three cell components within the lung metastatic niche, including CD163+ macrophages, neutrophils, and endothelial cells, expressed elevated levels of ApoE, leading to the secretion of various protumorigenic molecules that promote cancer cell growth in the lung. These molecules include galectin-1, S100A10, S100A4, and S100A6. Collectively, our findings highlight the lipid metabolism reprogramming of cancer and components of the tumor microenvironment that support lung metastasis of TNBC breast cancer.

DOI: https://doi.org/10.1038/s41419-024-07205-4
J Lipid Res. 2024 Dec 13. pii: S0022-2275(24)00234-7. [Epub ahead of print] 100729

Participation of lipids in the tumor response to photodynamic therapy and its exploitation for therapeutic gain.

Mladen Korbelik, Michal Heger, Albert W Girotti.

  Hydroperoxides of unsaturated membrane lipids (LOOHs) are the most abundant non-radical intermediates generated by photodynamic therapy (PDT) of soft tissues such as tumors and have far longer average lifetimes than singlet oxygen or oxygen radicals formed during initial photodynamic action. LOOH-initiated post-irradiation damage to remaining membrane lipids (chain peroxidation) or to membrane-associated proteins remains largely unrecognized. Such after-light processes could occur during clinical oncological PDT, but this is not well-perceived by practitioners of this therapy. In general, the pivotal influence of lipids in tumor responses to PDT needs to be better appreciated. Of related importance is the fact that most malignant tumors have dramatically different lipid metabolism compared with healthy tissues, and this is often ignored. The response of tumors to PDT appears especially vulnerable to manipulations within the tumor lipid microenvironment. This can be exploited for therapeutic gain with oncological PDT, as exemplified here by the combined treatment with antitumor lipid edelfosine.

Keywords:  antitumor lipids; cancer treatment; lipid peroxidation; lipid signaling; membrane dysfunction; oxidative damage; oxidative stress; repair mechanisms; tumor lipid metabolism

DOI:  https://doi.org/10.1016/j.jlr.2024.100729
Cell Rep. 2024 Dec 18. pii: S2211-1247(24)01447-5. [Epub ahead of print]44(1): 115096

P-cadherin mechanoactivates tumor-mesothelium metabolic coupling to promote ovarian cancer metastasis.

Jing Ma, Sally Kit Yan To, Katie Sze Wai Fung, Kun Wang, Jiangwen Zhang, Alfonso Hing Wan Ngan, Susan Yung, Tak Mao Chan, Carmen Chak Lui Wong, Philip Pun Ching Ip, Ling Peng, Hong-Yan Guo, Chi Bun Chan, Alice Sze Tsai Wong.

  Cancer adhesion to the mesothelium is critical for peritoneal metastasis, but how metastatic cells adapt to the biomechanical microenvironment remains unclear. Our study demonstrates that highly metastatic (HM), but not non-metastatic, ovarian cancer cells selectively activate the peritoneal mesothelium. HM cells exert a stronger adhesive force on mesothelial cells via P-cadherin, an adhesion molecule abundant in late-stage tumors. Mechanical activation of P-cadherin enhances lipogenic gene expression and lipid content in HM cells through SREBP1. P-cadherin also induces glycolysis in the interacting mesothelium without affecting lipogenic activity, with the resulting lactate serving as a substrate for lipogenesis in HM cells. Nanodelivery of small interfering RNA (siRNA) targeting P-cadherin or MCT1/4 transporters significantly suppresses metastasis in mice. Moreover, increased fatty acid synthase levels in metastatic patient samples correlate with high P-cadherin expression, supporting enhanced de novo lipogenesis in the metastatic niche. This study reveals P-cadherin-mediated mechano-metabolic coupling as a promising target to restrain metastasis.

Keywords:  CP: Cancer; CP: Metabolism; P-cadherin; adhesion; glycolysis; lipogenesis; mechanotransduction; metabolic reprogramming; ovarian cancer; peritoneal metastasis; tumor mesothelium

DOI:  https://doi.org/10.1016/j.celrep.2024.115096
Pathol Oncol Res. 2024 ;30 1611948

Combination of farnesyl-transferase inhibition with KRAS G12D targeting breaks down therapeutic resistance in pancreatic cancer.

Eszter Molnár, Marcell Baranyi, Krisztina Szigeti, Luca Hegedűs, Fanni Bordás, Zsófia Gábriel, Gréta Petényi, József Tóvári, Balázs Hegedűs, József Tímár.

  Pancreatic adenocarcinoma is one of the deadliest forms of cancer with no effective therapeutic options. A KRAS mutation can be found in up to 90% of all pancreatic tumors, making it a promising therapeutic target. The introduction of new KRAS inhibitors has been a milestone in the history of KRAS mutant tumors; however, therapeutic resistance limits their efficacy. Thus, new therapeutic options, including combination therapies, are urgently needed. Recently, we have shown that KRAS G12C inhibitors in combination with farnesyl-transferase inhibitors exert synergistic antitumor effects. Here, we provide evidence for the feasibility of this combinational approach to break down resistance in KRAS G12D mutant pancreatic cancer. Although we have shown that the 3D environment dramatically sensitizes cells to MRTX1133 treatment, the synergistic effect of this drug combination is present in both 2D and 3D in the PANC1 pancreatic adenocarcinoma model, which showed high resistance to MRTX1133 in 2D. The effects of the combination treatment show an association with the inhibition of farnesylated regulatory proteins, including HRAS and RHEB, along with the expression level of KRAS. Our study warrants further investigation for the potential applicability of KRAS G12D inhibitors in combination with farnesyl-transferase inhibitors for the treatment of KRAS mutant pancreatic adenocarcinoma.

Keywords:  FTI; G12D mutant KRAS; KRAS inhibitor resistance; PDAC; combination therapy

DOI:  https://doi.org/10.3389/pore.2024.1611948
Cancers (Basel). 2024 Dec 04. pii: 4060. [Epub ahead of print]16(23):

Interfering Nuclear Protein Laminb1 Induces DNA Damage and Reduces Vemurafenib Resistance in Melanoma Cells In Vitro.

Yuan Li, Yuqing Feng, Dan Chen.

   BACKGROUND/OBJECTIVES: Drug resistance poses a substantial clinical challenge in melanoma treatment, yet the underlying mechanism remains elusive. Here, we report the novel role of laminB1, a nuclear structure protein, in regulating the response of BRAF-mutated melanoma cells to vemurafenib.
RESULTS: Our analysis of clinical samples and existing databases highlights the tight correlation between the laminB1 expression level and melanoma progression and prognosis. Notably, we observe that laminB1 expression is upregulated when BRAF-mutated melanoma cells develop resistance to vemurafenib. The knockdown of laminB1 substantially increases the sensitivity of melanoma cells to vemurafenib. Furthermore, we found laminB1 suppression increases cell apoptosis via the escalation of DNA damage in a vemurafenib-dose-dependent manner. Conversely, protective cell autophagy is negatively regulated by laminB1 suppression. Interestingly, this distinct regulation pattern of apoptosis and autophagy by laminB1 cooperatively promotes the response of BRAF-mutated melanoma cells to vemurafenib.
CONCLUSIONS: Our findings unveil the potential of laminB1 as both a diagnosis marker and a therapeutic target of melanoma.

Keywords:  BRAF inhibitors; DNA damage; laminb1; melanoma

DOI:  https://doi.org/10.3390/cancers16234060
Biochem Biophys Res Commun. 2024 Dec 05. pii: S0006-291X(24)01677-2. [Epub ahead of print]743 151141

Mitochondrial-targeting strategies with homoharringtonine: A novel approach for chemoresistant rectal cancer.

Hu Chenghao, Liu Xuefeng, Pang Junli, Wang Ke, Li Haixia, Hu Guangyue, Luo Qingqin, Wu Feng.

  5-Fluorouracil (5-FU) resistance poses a significant challenge in the treatment of rectal cancer, driving the need for novel therapeutic strategies. In this study, we established 5-FU-resistant rectal cancer cell lines (SW837-r, SNU-C1-r) and identified homoharringtonine (HHT) as a potent and selective anticancer agent through high-throughput drug screening of 291 compounds. HHT displayed the highest selective drug sensitivity score (sDSS), showing strong activity against resistant cells while sparing normal rectal epithelial cells. Further investigations revealed that 5-FU-resistant cells exhibited enhanced mitochondrial biogenesis and function compared to normal cells, and HHT exerted its cytotoxic effects by targeting mitochondrial respiration. HHT significantly reduced oxygen consumption rate (OCR), mitochondrial complex I activity, and ATP production in resistant cells, with mitochondrial respiration-deficient ρ0 cells showing reduced sensitivity to HHT. In vivo, HHT alone reduced tumor growth by 60 % in the resistant xenograft model. In the sensitive xenograft model, combination therapy with 5-FU achieved an 85 % reduction in tumor volume compared to controls, with tumors in the combination group displaying minimal regrowth. These results demonstrate that HHT effectively targets mitochondrial function in resistant rectal cancer cells and, in combination with 5-FU, offers synergistic antitumor effects and prolonged tumor suppression. The favorable safety profile of HHT further highlights its potential as a promising therapeutic agent for overcoming 5-FU resistance in rectal cancer.

Keywords:  5-FU resistance; DSS; HHT; High-throughput drug screening; Mitochondrial respiration; Rectal cancer

DOI:  https://doi.org/10.1016/j.bbrc.2024.151141