bims-nurfca 2024-01-28 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024‒01‒28
fifteen papers selected by
Caner Geyik, Istinye University

Distinct mechanisms by which Nrf1 and Nrf2 as drug targets contribute to the anticancer efficacy of cisplatin on hepatoma cells.
NRF2 mutation enhances the immune escape of hepatocellular carcinoma by reducing STING activation.
The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?
SN-38, an active metabolite of irinotecan, inhibits transcription of nuclear factor erythroid 2-related factor 2 and enhances drug sensitivity of colorectal cancer cells.
Auranofin sensitizes breast cancer cells to paclitaxel mediated cell death via regulating FOXO3/Nrf2/Keap1 signaling pathway.
The Tumor Suppressor SOCS1 Diminishes Tolerance to Oxidative Stress in Hepatocellular Carcinoma.
NOP16 promotes hepatocellular carcinoma progression and triggers EMT through the Keap1-Nrf2 signaling pathway.
Post-translational modifications of Keap1: the state of the art.
Paris saponin VII promotes ferroptosis to inhibit breast cancer via Nrf2/GPX4 axis.
PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.
Tremella fuciformis polysaccharides induce ferroptosis in Epstein-Barr virus-associated gastric cancer by inactivating NRF2/HO-1 signaling.
Selection of GalNAc-Conjugated siKeap1 as Disease-Specific Delivery System for Chemotherapy-Induced Liver Injury and Chronic Liver Disease.
Glutathione Depletion-Induced Versatile Nanomedicine for Potentiating The Ferroptosis to Overcome Solid Tumor Radioresistance And Enhance Immunotherapy.
Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors.
CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in Opisthorchis viverrini-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS.

Free Radic Biol Med. 2024 Jan 24. pii: S0891-5849(24)00039-X. [Epub ahead of print]

Distinct mechanisms by which Nrf1 and Nrf2 as drug targets contribute to the anticancer efficacy of cisplatin on hepatoma cells.

Reziyamu Wufuer, Keli Liu, Jing Feng, Meng Wang, Shaofan Hu, Feilong Chen, Shanshan Lin, Yiguo Zhang.

  Cisplatin (cis-Dichlorodiamineplatinum[II], CDDP) is generally accepted as a platinum-based alkylating agent type of the DNA-damaging anticancer drug, which is widely administrated in clinical treatment of many solid tumors. The pharmacological effect of CDDP is mainly achieved by replacing the chloride ion (Cl-) in its structure with H2O to form active substances with the strong electrophilic properties and then react with any nucleophilic molecules, primarily leading to genomic DNA damage and subsequent cell death. In this process, those target genes driven by the consensus electrophilic and/or antioxidant response elements (EpREs/AREs) in their promoter regions are also activated or repressed by CDDP. Thereby, we here examined the expression profiling of such genes regulated by two principal antioxidant transcription factors Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) in diverse cellular signaling responses to this intervention. The results demonstrated distinct cellular metabolisms, molecular pathways and signaling response mechanisms by which Nrf1 and Nrf2 as the drug targets differentially contribute to the anticancer efficacy of CDDP on hepatoma cells and xenograft tumor mice. Interestingly, the role of Nrf1, rather than Nrf2, is required for the anticancer effect of CDDP, to suppress malignant behavior of HepG2 cells by differentially monitoring multi-hierarchical signaling to gene regulatory networks. To our surprise, it was found there exists a closer relationship of Nrf1α than Nrf2 with DNA repair, but the hyperactive Nrf2 in Nrf1α-∕- cells manifests a strong correlation with its resistance to CDDP, albeit their mechanistic details remain elusive.

Keywords:  Cell metabolism; Cisplatin; DNA repair; Drug resistance; Gene regulation; Nrf1; Nrf2; Redox signaling

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.031
Biochem Biophys Res Commun. 2024 Jan 17. pii: S0006-291X(24)00071-8. [Epub ahead of print]698 149536

NRF2 mutation enhances the immune escape of hepatocellular carcinoma by reducing STING activation.

Cheng Li, Gang Liang, Ke Yan, Yongheng Wang.

  The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor usually hyperactivated in hepatocellular carcinoma (HCC). In addition, about 14 % of HCC patients carry mutation in NRF2 or Kelch-like ECH-associated protein 1 (Keap1), a NRF2 inhibitor, both of which lead to constitutive activation of NRF2. It has been widely reported that NRF2 plays important roles in the proliferation, differentiation and metastasis of tumor cells. But as an important gene involved in antioxidation and anti-inflammation, little studies have focused on its role in tumor immune escape. Here we found that NRF2 gain-of-function mutation leads to reduced expression of STING and decreased infiltration of peripheral immune cells through which way it helps the tumor cells to evade from immune surveillance. This phenomenon can be reversed by STING overexpression. Our study also revealed that NRF2 mutation greatly reduced the effect of STING activating based immunotherapy. It is important to simultaneously inhibit the activity of NRF2 when using STING agonist for the treatment of HCC patients carrying NRF2 mutation.

Keywords:  Hepatocellular carcinoma; Immune escape; Immunotherapy; NRF2; STING

DOI:  https://doi.org/10.1016/j.bbrc.2024.149536
Antioxidants (Basel). 2024 Jan 02. pii: 70. [Epub ahead of print]13(1):

The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?

Christophe Glorieux, Cinthya Enríquez, Constanza González, Gabriela Aguirre-Martínez, Pedro Buc Calderon.

  Physiological concentrations of reactive oxygen species (ROS) play vital roles in various normal cellular processes, whereas excessive ROS generation is central to disease pathogenesis. The nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor that regulates the cellular antioxidant systems in response to oxidative stress by governing the expression of genes encoding antioxidant enzymes that shield cells from diverse oxidative alterations. NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) have been the focus of numerous investigations in elucidating whether NRF2 suppresses tumor promotion or conversely exerts pro-oncogenic effects. NRF2 has been found to participate in various pathological processes, including dysregulated cell proliferation, metabolic remodeling, and resistance to apoptosis. Herein, this review article will examine the intriguing role of phase separation in activating the NRF2 transcriptional activity and explore the NRF2 dual impacts on tumor immunology, cancer stem cells, metastasis, and long non-coding RNAs (LncRNAs). Taken together, this review aims to discuss the NRF2 multifaceted roles in both cancer prevention and promotion while also addressing the advantages, disadvantages, and limitations associated with modulating NRF2 therapeutically in cancer treatment.

Keywords:  LncRNA; NRF2; NRF2 activators; NRF2 inhibitors; cancer; metabolism; metastasis; natural compounds; phase separation; tumor immunology

DOI:  https://doi.org/10.3390/antiox13010070
Mol Carcinog. 2024 Jan 25.

SN-38, an active metabolite of irinotecan, inhibits transcription of nuclear factor erythroid 2-related factor 2 and enhances drug sensitivity of colorectal cancer cells.

Jingya Wang, Jiangli Xu, Shuhui Yang, Liu He, Wenhuai Xu, Yan'e Liu, Baoshan Cao, Siwang Yu.

  Nuclear factor erythroid 2-related factor 2 (Nrf2) significantly contributes to drug resistance of cancer cells, and Nrf2 inhibitors have been vigorously pursued. Repurposing of existing drugs, especially anticancer drugs, is a straightforward and promising strategy to find clinically available Nrf2 inhibitors and effective drug combinations. Topoisomerase inhibitors SN-38 (an active metabolite of irinotecan), topotecan, mitoxantrone, and epirubicin were found to significantly suppress Nrf2 transcriptional activity in cancer cells. SN-38, the most potent one among them, significantly inhibited the transcription of Nrf2, as indicated by decreased mRNA level and binding of RNA polymerase II to NFE2L2 gene, while no impact on Nrf2 protein or mRNA degradation was observed. SN-38 synergized with Nrf2-sensitive anticancer drugs such as mitomycin C in killing colorectal cancer cells, and irinotecan and mitomycin C synergistically inhibited the growth of SW480 xenografts in nude mice. Our study identified SN-38 and three other topoisomerase inhibitors as Nrf2 inhibitors, revealed the Nrf2-inhibitory mechanism of SN-38, and indicate that clinically feasible drug combinations could be designed based on their interactions with Nrf2 signaling.

Keywords:  Nrf2 inhibitor; chemo-sensitization; colorectal cancer; irinotecan; topoisomerase inhibitor

DOI:  https://doi.org/10.1002/mc.23685
Cell Biochem Funct. 2024 Jan;42(1): e3903

Auranofin sensitizes breast cancer cells to paclitaxel mediated cell death via regulating FOXO3/Nrf2/Keap1 signaling pathway.

N Deepika, N Rajendra Prasad, T Radhiga.

  Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor which acts as a regulator for cellular oxidative stress, and tightly regulated by Kelch-like ECH-associated protein 1 (Keap1). In this study, we found that auranofin and paclitaxel combination treatment increased TUNEL positive apoptotic cells and enhanced the DNA damage marker γ-H2AX in MCF-7 and MDA-MB-231 breast cancer cells. The immunoblotting analysis revealed the combination of auranofin and paclitaxel significantly increased the FOXO3 expression in a concentration dependent manner. Further we observed that auranofin and paclitaxel treatment prevents the translocation of Nrf2 in a concentration dependent manner. The increased FOXO3 expression might be involved in the cytoplasmic degradation of Nrf1-Keap1 complex. Further, the molecular docking results confirm auranofin act as the agonist for Foxo3. Therefore, the present results suggest that auranofin sensitize the breast cancer cells to paclitaxel via regulating FOXO3/Nrf2/Keap1signaling pathway.

Keywords:  Nrf2 pathway; antioxidants; auranofin; breast cancer; paclitaxel

DOI:  https://doi.org/10.1002/cbf.3903
Cancers (Basel). 2024 Jan 10. pii: 292. [Epub ahead of print]16(2):

The Tumor Suppressor SOCS1 Diminishes Tolerance to Oxidative Stress in Hepatocellular Carcinoma.

Akhil Shukla, Md Gulam Musawwir Khan, Anny Armas Cayarga, Mozhdeh Namvarpour, Mohammad Mobarak H Chowdhury, Dominique Levesque, Jean-François Lucier, François-Michel Boisvert, Sheela Ramanathan, Subburaj Ilangumaran.

  SOCS1 is a tumor suppressor in hepatocellular carcinoma (HCC). Recently, we showed that a loss of SOCS1 in hepatocytes promotes NRF2 activation. Here, we investigated how SOCS1 expression in HCC cells affected oxidative stress response and modulated the cellular proteome. Murine Hepa1-6 cells expressing SOCS1 (Hepa-SOCS1) or control vector (Hepa-Vector) were treated with cisplatin or tert-butyl hydroperoxide (t-BHP). The induction of NRF2 and its target genes, oxidative stress, lipid peroxidation, cell survival and cellular proteome profiles were evaluated. NRF2 induction was significantly reduced in Hepa-SOCS1 cells. The gene and protein expression of NRF2 targets were differentially induced in Hepa-Vector cells but markedly suppressed in Hepa-SOCS1 cells. Hepa-SOCS1 cells displayed an increased induction of reactive oxygen species but reduced lipid peroxidation. Nonetheless, Hepa-SOCS1 cells treated with cisplatin or t-BHP showed reduced survival. GCLC, poorly induced in Hepa-SOCS1 cells, showed a strong positive correlation with NFE2L2 and an inverse correlation with SOCS1 in the TCGA-LIHC transcriptomic data. A proteomic analysis of Hepa-Vector and Hepa-SOCS1 cells revealed that SOCS1 differentially modulated many proteins involved in diverse molecular pathways, including mitochondrial ROS generation and ROS detoxification, through peroxiredoxin and thioredoxin systems. Our findings indicate that maintaining sensitivity to oxidative stress is an important tumor suppression mechanism of SOCS1 in HCC.

Keywords:  NRF2; SOCS1; cisplatin; hepatocellular carcinoma; mass spectrometry; oxidative stress; tert-butyl hydroperoxide; tumor suppressor

DOI:  https://doi.org/10.3390/cancers16020292
Technol Health Care. 2024 Jan 04.

NOP16 promotes hepatocellular carcinoma progression and triggers EMT through the Keap1-Nrf2 signaling pathway.

Shangdong Mu, Qiusi Tian, Liangyu Shen.

  BACKGROUND: Nucleolar protein 16 (NOP16) is present in the protein complex of the nucleolus. The NOP16 promoter contains a c-Myc binding site, and the transcriptional regulation by c-Myc directly regulates NOP16 expression levels.OBJECTIVE: Dysregulation of NOP 16 is currently reported in only a small number of cancers. In this study, the expression profile of NOP 16 in hepatocellular carcinoma (LIHC) and its clinical significance were analyzed.
METHODS: NOP16 expression in hepatocellular carcinoma (LIHC) and its relationship with the clinical characters of LIHC were examined using the Cancer Genome Atlas (TCGA), the Gene Expression comprehensive database (GEO), Kaplan-Meier survival analysis, univariate Cox analysis, multivariate Cox analysis, ROC curve analysis of KEGG enrichment, GSEA enrichment, in vitro experiments (e.g., siRNA interference of NOP16 expression in hepatoma cells, Keap1-Nrf2 pathway, cell cycle, cell apoptosis and Transwell assays), and LIHC single-cell sequencing (scRNA).
RESULTS: Pan-cancer analysis revealed that NOP16 was highly expressed in 20 cancer types, including LIHC, and high NOP16 expression was an independent adverse prognostic factor in LIHC patients. The expression levels of NOP16 mRNA and protein were significantly increased in tumour tissues of LIHC patients compared to normal tissues. The functions of co-expressed genes were primarily enriched in the cell cycle and reactive oxygen species metabolism. The experimental results showed that knockdown of NOP16 activated the Keap/Nrf2 signalling pathway and inhibited the invasion, migration, and EMT progression of LIHC cells. LIHC scRNA-seq data showed that NOP16 was primarily expressed in T lymphocytes.
CONCLUSIONS: NOP16 promoted cancer development in LIHC and caused an imbalance in Keap/Nrf2 signalling, which subsequently caused the aberrant expression of genes typical for EMT, cell cycle progression and apoptosis. NOP16 is a potential prognostic marker and therapeutic target for hepatocellular carcinoma progression.

Keywords:  Keap1-Nrf2 pathway; NOP16; bioinformatics; hepatic cell liver cancer

DOI:  https://doi.org/10.3233/THC-231256
Front Cell Dev Biol. 2023 ;11 1332049

Post-translational modifications of Keap1: the state of the art.

Yunjia Song, Ying Qu, Caiyun Mao, Rong Zhang, Deyou Jiang, Xutao Sun.

  The Keap1-Nrf2 signaling pathway plays a crucial role in cellular defense against oxidative stress-induced damage. Its activation entails the expression and transcriptional regulation of several proteins involved in detoxification and antioxidation processes within the organism. Keap1, serving as a pivotal transcriptional regulator within this pathway, exerts control over the activity of Nrf2. Various post-translational modifications (PTMs) of Keap1, such as alkylation, glycosylation, glutathiylation, S-sulfhydration, and other modifications, impact the binding affinity between Keap1 and Nrf2. Consequently, this leads to the accumulation of Nrf2 and its translocation to the nucleus, and subsequent activation of downstream antioxidant genes. Given the association between the Keap1-Nrf2 signaling pathway and various diseases such as cancer, neurodegenerative disorders, and diabetes, comprehending the post-translational modification of Keap1 not only deepens our understanding of Nrf2 signaling regulation but also contributes to the identification of novel drug targets and biomarkers. Consequently, this knowledge holds immense importance in the prevention and treatment of diseases induced by oxidative stress.

Keywords:  Keap1; Nrf2; biomarker; oxidative stress; post-translational modification

DOI:  https://doi.org/10.3389/fcell.2023.1332049
Biochem Biophys Res Commun. 2024 Jan 12. pii: S0006-291X(24)00059-7. [Epub ahead of print]697 149524

Paris saponin VII promotes ferroptosis to inhibit breast cancer via Nrf2/GPX4 axis.

Chen Yan, Fei Xuan.

  Breast cancer (BC) is one of the malignancies threatening the woman's health. Our study aims to explore the underlying mechanism behind the anti-tumor function of Paris saponin VII (PS VII) in BC. Xenografting experiment was conducted to monitor the tumor growth. The Ki67 and 4-HNE expression were analyzed via immunohistochemical assay. After different treatments, the cell viability, proliferation, invasion, and migration capacity of BC cells were measured by the CCK-8, colony formation, transwell, and wound healing assays, respectively. The ratio of GSH/GSSG was measured by the GSH/GSSG ratio detection assay kit. The lipid ROS and Fe2+ levels were quantified by flow cytometry analysis. The expressions of TFR1, ACSL4, Nrf2, and GPX4 were measured via western blotting. Compared with the Ctrl group, the tumor volumes, and Ki67 expression were markedly reduced in PS VII groups, and the BC cell viability was decreased by PS VII treatment in a dose-dependent manner. The colony numbers, invasive cells, and migration rates were also significantly decreased by PS VII treatment. Then, the Nrf2 as well as GPX4 expressions were decreased and TFR1 expression was increased by PS VII treatment in vitro and in vivo, while there was no difference in ACSL4 expression between Ctrl and PS VII groups. Moreover, the above effects of PS VII could not be observed in GPX4 knockdown cells. PS VII can promote ferroptosis to inhibit BC via the Nrf2/GPX4 axis, which innovatively suggests the pro-ferroptosis effect and therapeutic potential of PS VII in BC.

Keywords:  Breast cancer; Effect; Ferroptosis; Nrf2/GPX4; Paris saponin VII

DOI:  https://doi.org/10.1016/j.bbrc.2024.149524
Blood. 2024 Jan 25. pii: blood.2023022202. [Epub ahead of print]

PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.

Hao Gu, Chiqi Chen, Zhi-Shuai Hou, Xia-Di He, Shaozhen Xie, Jing Ni, Changli Qian, Xin Cheng, Tao Jiang, Ce Yang, Thomas M Roberts, Junke Zheng, Judith A Varner, Scott A Armstrong, Jean J Zhao.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem/progenitor cells. AML prognosis remains poor, due to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The PI3K/AKT pathway is often dysregulated in AML. We found while that PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes NRF2 nuclear accumulation, which induces PGD and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may therefore eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.

DOI: https://doi.org/10.1182/blood.2023022202
Aging (Albany NY). 2024 Jan 19. 15

Tremella fuciformis polysaccharides induce ferroptosis in Epstein-Barr virus-associated gastric cancer by inactivating NRF2/HO-1 signaling.

Wencheng Kong, Xinchun Liu, Hangzhang Zhu, Sixing Zheng, Guang Yin, Panpan Yu, Yuqiang Shan, Shenglin Ma, Rongchao Ying, Huicheng Jin.

  Approximately 10% of gastric cancers are associated with Epstein-Barr virus (EBV). Tremella fuciformis polysaccharides (TFPs) are characterized by antioxidative and anti-inflammatory effects in different diseases. However, whether TFP improves EBV-associated gastric cancer (EBVaGC) has never been explored. The effects of TFP on EBV-infected GC cell viability were determined using a CCK-8 assay and flow cytometry. Western blotting and RT-qPCR were performed to explore the expression of ferroptosis-related proteins. The CCK-8 assay showed that TFP decreased EBV-infected GC cell viability in a dose- and time-dependent manner. Flow cytometry assays indicated that TFP significantly induced EBV-infected GC cell death. TFP also reduced the migratory capacity of EBV-infected GC cells. Furthermore, treatment with TFP significantly increased the mRNA levels of PTGS2 and Chac1 in EBV-infected GC cells. Western blot assays indicated that TFP suppressed the expression of NRF2, HO-1, GPX4 and xCT in EBV-infected GC cells. More importantly, overexpression of NRF2 could obviously rescue TFP-induced downregulation of GPX4 and xCT in EBV-infected GC cells. In summary, we showed novel data that TFP induced ferroptosis in EBV-infected GC cells by inhibiting NRF2/HO-1 signaling. The current findings may shed light on the potential clinical application of TFP in the treatment of EBVaGC.

Keywords:  Epstein-Barr virus-associated gastric cancer; NRF2/HO-1; Tremella fuciformis polysaccharides; ferroptosis

DOI:  https://doi.org/10.18632/aging.205457
Nano Lett. 2024 Jan 22.

Selection of GalNAc-Conjugated siKeap1 as Disease-Specific Delivery System for Chemotherapy-Induced Liver Injury and Chronic Liver Disease.

Mengmeng You, Meng Tian, Zhiling Song, Zhen Liu, Bingxue Yang, Shiyi Zhang.

  Chemotherapy-induced liver injury (CILI) is a pressing concern in cancer patients. One promising approach involves activating nuclear factor erythroid 2-related factor 2 (Nrf2) to mitigate CILI. However, selectively activating liver Nrf2 without compromising chemotherapy's efficacy has remained elusive. Herein, two RNAi delivery strategies were explored: lipid nanoparticle (LNP) and N-acetylgalactosamine (GalNAc) delivery systems loaded with siRNA designed to silence Kelch-like-ECH associated protein 1 (Keap1) by aiming for liver-specific Nrf2 activation. Remarkably, siKeap1-LNP exhibited unintended tumor targeting alongside liver effects, thereby potentially promoting tumor progression. Conversely, siKeap1-GalNAc did not compromise chemotherapy efficacy and outperformed the conventional Nrf2 activator, bardoxolone, in mitigating CILI. This study proposes siKeap1-GalNAc as a promising therapeutic avenue for liver injury. Importantly, our study bridges a crucial gap concerning the delivery system for liver targeting but not tumor targeting and underscores the importance of selecting nucleic acid delivery systems tailored to specific diseases, not just to specific organs.

Keywords:  GalNAc; LNP; Nrf-2; chemotherapy-induced liver injury; siRNA therapeutics

DOI:  https://doi.org/10.1021/acs.nanolett.3c03609
Adv Healthc Mater. 2024 Jan 21. e2303412

Glutathione Depletion-Induced Versatile Nanomedicine for Potentiating The Ferroptosis to Overcome Solid Tumor Radioresistance And Enhance Immunotherapy.

Huijuan Song, Hao Sun, Ningning He, Chang Xu, Liqing Du, Kaihua Ji, Jinhan Wang, Manman Zhang, Yeqing Gu, Yan Wang, Qiang Liu.

  A high level of reduced glutathione is a major factor contributing to the radioresistance observed in solid tumors. To address this radioresistance associated with glutathione, we fabricated a cinnamaldehyde (CA) polymer prodrug, referred to as PDPCA. This prodrug was created by synthesizing a pendent CA prodrug with acetal linkages in a hydrophobic block, forming a self-assembled into a core-shell nanoparticle in aqueous media. Additionally, it encapsulated all-trans retinoic acid (ATRA) for synchronous delivery, resulting in PDPCA@ATRA. The PDPCA@ATRA nanoparticles accumulated reactive oxygen species through both endogenous and exogenous pathways, enhancing ferroptosis by depleting glutathione. This approach has demonstrated efficacy in overcoming tumor radioresistance in vivo and in vitro and promoting the ferroptosis and enhancing the cytotoxic T lymphocyte (CTL) response for lung tumors to anti-PD-1 (αPD-1) immunotherapy. Furthermore, this study revealed that PDPCA@ATRA nanoparticles promoted ferroptosis through the NRF2-GPX4 signaling pathway, suggeating the potential for further investigation into the combination of radiotherapy and αPD-1 immune checkpoint inhibitors in cancer treatment. This article is protected by copyright. All rights reserved.

Keywords:  Anti-PD-1; ROS; ferroptosis; glutathione; radioresistance

DOI:  https://doi.org/10.1002/adhm.202303412
Int J Hematol. 2024 Jan 21.

Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors.

Kimiko Sogabe, Shingen Nakamura, Yoshiki Higa, Hirokazu Miki, Asuka Oda, Tomoko Maruhashi, Ryohei Sumitani, Masahiro Oura, Mamiko Takahashi, Masafumi Nakamura, Yusaku Maeda, Tomoyo Hara, Hiroki Yamagami, Shiro Fujii, Kumiko Kagawa, Shuji Ozaki, Kiyoe Kurahashi, Itsuro Endo, Ken-Ichi Aihara, Emiko Nakaue, Masahiro Hiasa, Jumpei Teramachi, Takeshi Harada, Masahiro Abe.

  Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of β5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of β5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.

Keywords:  Multiple myeloma; NRF2; PIM2; Proteasome inhibitor; β5 subunit activity

DOI:  https://doi.org/10.1007/s12185-023-03705-9
Pharmaceuticals (Basel). 2023 Dec 20. pii: 9. [Epub ahead of print]17(1):

CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in Opisthorchis viverrini-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS.

Jinchutha Duangdara, Boonyakorn Boonsri, Apinya Sayinta, Kittiya Supradit, Pakpoom Thintharua, Supeecha Kumkate, Chinnawut Suriyonplengsaeng, Noppadol Larbcharoensub, Somkit Mingphruedhi, Narongsak Rungsakulkij, Paramin Muangkaew, Pongsatorn Tangtawee, Watoo Vassanasiri, Wikran Suragul, Tavan Janvilisri, Rutaiwan Tohtong, David O Bates, Kanokpan Wongprasert.

  Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) play essential roles in promoting cholangiocarcinoma (CCA) cell survival by mediating paracrine crosstalk between tumor and cancer-associated fibroblasts (CAFs), indicating the potential of PDGFR as a target for CCA treatment. Clinical trials evaluating PDGFR inhibitors for CCA treatment have shown limited efficacy. Furthermore, little is known about the role of PDGF/PDGFR expression and the mechanism underlying PDGFR inhibitors in CCA related to Opisthorchis viverrini (OV). Therefore, we examined the effect of PDGFR inhibitors in OV-related CCA cells and investigated the molecular mechanism involved. We found that the PDGF and PDGFR mRNAs were overexpressed in CCA tissues compared to resection margins. Notably, PDGFR-α showed high expression in CCA cells, while PDGFR-β was predominantly expressed in CAFs. The selective inhibitor CP-673451 induced CCA cell death by suppressing the PI3K/Akt/Nrf2 pathway, leading to a decreased expression of Nrf2-targeted antioxidant genes. Consequently, this led to an increase in ROS levels and the promotion of CCA apoptosis. CP-673451 is a promising PDGFR-targeted drug for CCA and supports the further clinical investigation of CP-673451 for CCA treatment, particularly in the context of OV-related cases.

Keywords:  CP-673451; Nrf2; Opisthorchis viverrini; PDGFR inhibitor; cholangiocarcinoma

DOI:  https://doi.org/10.3390/ph17010009