bims-meproc 2026-05-10 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–05–10
eight papers selected by
Grigor Varuzhanyan, UCLA

Oncogenic MAGEA4 directs neuroendocrine differentiation and survival in prostate cancer cells through the SIRT1/Acetyl-p53/BCL-2 axis.
Single Cell and Bulk RNA-Seq Profiling of Non-Metastatic Versus Bone-Metastatic Prostate Cancer Identifies the CXCL10-CXCR3 Axis as a Key Determinant of Tumor Microenvironment and Treatment Resistance.
GUTK induces apoptosis in reactivating quiescent prostate cancer cells via Aurora A-mediated stabilization of SOD2.
Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.
DNMT1-DUOXA1 axis discovers a novel methylation-ferroptosis circuit in bicalutamide-resistant prostate cancer.
Breaking the bonds: targeting protein dimerization for prostate cancer therapy.
Indirubin Sensitizes Prostate Cancer to Docetaxel by Inhibiting Autophagy Through the circ-Vav3/miR-204-5p/MAPK1 Pathway.
NLRX1 Drives Prostate Cancer Progression Through Activation of AKT and ERK Signaling Pathways.

Mol Biol Rep. 2026 May 05. pii: 710. [Epub ahead of print]53(1):

Oncogenic MAGEA4 directs neuroendocrine differentiation and survival in prostate cancer cells through the SIRT1/Acetyl-p53/BCL-2 axis.

Maresha Ramakrishna, Teja Nallavolu, Ramesh Ummanni.

   BACKGROUND: Neuroendocrine prostate cancer (NEPC) is a highly aggressive and therapy-resistant subtype of prostate cancer (PCa) that emerges following the androgen receptor (AR) targeted therapies. Identification of potential molecular drivers governing neuroendocrine differentiation (NED) and survival is critical for developing therapeutic strategies. Cancer-testis antigens of the Melanoma-associated antigen family (MAGE) are the emerging players of oncogenic regulators. However, their role in NEPC remains unexplored.
METHODS: Proteomic and transcriptomic analyses were performed to identify differential expression of target proteins in NEPC. Functional characterization of MAGEA4 was performed using stable overexpression, siRNA-mediated knockdown in androgen-dependent/independent, and NEPC cell lines. For target validation, neuroendocrine markers, morphological characteristics, apoptotic signaling, oxidative pathways, and cell survival were evaluated using molecular, biochemical, and pharmacological approaches targeting SIRT1, p53 acetylation, BCL-2/BCL-XL and NRF2.
RESULTS: MAGEA4 was upregulated in NEPC cells and in advanced prostate cancer tissues. Overexpression of MAGEA4 induced neuroendocrine differentiation, promoted androgen-independent survival, and conferred resistance to apoptosis. Furthermore, MAGEA4 upregulated SIRT1 activity, which deacetylated p53, thereby suppressing pro-apoptotic signaling. Additionally, MAGEA4 enhanced the oxidative stress resistance through activation of the SIRT1/PGC-1α/NRF2 axis, suggesting a role in retaining the NED phenotype. In MAGEA4-positive cells, inhibition of BCL-2 and/or NRF2 attenuated the neuroendocrine characteristics, suggesting therapeutic vulnerability.
CONCLUSION: These findings highlight that MAGEA4 may contribute to neuroendocrine differentiation and survival in prostate cancer cells, and may represent a potential therapeutic vulnerability in aggressive prostate cancers.

Keywords:  Acetyl p53; BCL-2; MAGEA4; NE-LNCaP and NCI-H660; NRF2; SIRT1

DOI:  https://doi.org/10.1007/s11033-026-11878-9
Biomedicines. 2026 Apr 21. pii: 943. [Epub ahead of print]14(4):

Single Cell and Bulk RNA-Seq Profiling of Non-Metastatic Versus Bone-Metastatic Prostate Cancer Identifies the CXCL10-CXCR3 Axis as a Key Determinant of Tumor Microenvironment and Treatment Resistance.

Zijian Song, Likai Ren, Hong Wang, Yanqing Wang, Xinxing Du, Wei Zhou, Qi Zhang, Jiyuan Yu, Zaixu Zhao, Linxiong Ye, Kaidi Jin, Ying Liu, Wei Xue.

  Background: Bone metastasis is a major determinant of morbidity and therapeutic failure in advanced prostate cancer (PCa); however, the transcriptional programs and tumor microenvironmental alterations driving metastatic progression remain incompletely understood. This study aimed to systematically characterize transcriptomic differences between non-metastatic and bone-metastatic PCa and to identify key microenvironmental signaling pathways involved in tumor survival and chemoresistance. Methods: Bulk RNA sequencing was performed on 49 non-metastatic and 28 bone-metastatic PCa specimens. Differential expression analysis was integrated with weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis, and immune/stromal deconvolution. Key findings were validated using in vitro functional assays, including Transwell co-culture models, small interfering RNA (siRNA)-mediated gene silencing, cell viability, apoptosis, and docetaxel resistance analyses. Results: Transcriptomic profiling identified 574 differentially expressed genes. Bone-metastatic tumors were enriched in ribosome-related and translational pathways, whereas non-metastatic tumors displayed immune-associated signatures, including natural killer (NK) cell-mediated cytotoxicity and cytokine signaling. WGCNA revealed immune-related gene modules preferentially enriched in non-metastatic disease. Immune deconvolution demonstrated significantly higher infiltration of NK cells and endothelial cells in non-metastatic tumors. Chemokine-receptor analysis highlighted upregulation of the CXCL10-CXCR3 axis in non-metastatic PCa. In vitro, PCa cells expressed CXCR3, while endothelial cells markedly increased CXCL10 expression upon co-culture. Functional assays showed that endothelial-derived CXCL10 promoted PCa cell survival, suppressed apoptosis, and conferred resistance to docetaxel via CXCR3-dependent signaling; these effects were reversed by CXCL10 or CXCR3 knockdown. Conclusions: These findings uncover a context-dependent endothelial-immune chemokine network distinguishing non-metastatic from bone-metastatic PCa and identify the CXCL10-CXCR3 axis as a critical mediator of tumor survival and chemoresistance, suggesting a potential therapeutic vulnerability in advanced prostate cancer.

Keywords:  CXCL10-CXCR3 axis; bone metastasis; bulk RNA sequencing; prostate cancer; single-cell sequencing; tumor microenvironment

DOI:  https://doi.org/10.3390/biomedicines14040943
iScience. 2026 May 15. 29(5): 115739

GUTK induces apoptosis in reactivating quiescent prostate cancer cells via Aurora A-mediated stabilization of SOD2.

Yalin Wang, Yang Li, Xue Jiang, Xiaoqiong Chen, Mengfan Liu, Hangui Ren, Yulong Zhang, Rongchen Dai, Zhichao Xi, Hongxi Xu.

  Quiescent prostate cancer (PCa) cells that survive therapy can later reactivate and drive tumor recurrence and metastasis. Here, we identify a strategy to eliminate these cells during their vulnerable reactivation phase. We show that guttiferone K (GUTK), a bioactive compound isolated from Garcinia yunnanensis Hu, selectively eradicates reactivating quiescent PCa cells by inducing mitochondrial apoptosis through caspase activation and loss of mitochondrial membrane potential (ΔΨm). Mechanistically, GUTK suppresses Aurora A recovery and stabilizes SOD2 protein, thereby promoting mitochondrial dysfunction and apoptosis. SOD2 enhances, whereas Aurora A overexpression attenuates, GUTK-induced cell death. In orthotopic and xenograft prostate tumor models, GUTK combined with docetaxel significantly inhibits tumor growth and suppresses post-chemotherapy recurrence without evident toxicity. These findings identify GUTK as a potential therapeutic agent targeting reactivating quiescent PCa cells and highlight the Aurora A-SOD2 axis as a promising pathway for preventing PCa recurrence.

Keywords:  biochemistry; cancer; pharmacology

DOI:  https://doi.org/10.1016/j.isci.2026.115739
Mol Cancer Ther. 2026 May 05. OF1-OF13

Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.

Zachary A Schaaf, Shu Ning, Amy R Leslie, Masuda Sharifi, Richard Y Gao, James P Maine, Kristina D Leslie, Yuqiu Shen, Alan P Lombard, Wei Lou, Pui-Kai Li, Chengfei Liu, Marc Dall'Era, Allen C Gao.

Resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) remains a major challenge in the treatment of advanced prostate cancer. Although metabolic rewiring has been implicated in this process, the molecular drivers and therapeutic vulnerabilities underlying this adaptation remain poorly defined. We integrated transcriptomic, functional, and clinical analyses to identify mitochondrial regulators of PARPi resistance. RNA sequencing and gene set enrichment analysis revealed robust enrichment of oxidative phosphorylation (OxPhos) pathways in PARPi-resistant prostate cancer cells, with consistent upregulation of NDUFS4, a nuclear-encoded subunit of electron transport chain complex I. Elevated NDUFS4 expression correlated with poor survival in patient cohorts from The Cancer Genome Atlas and SU2C/PCF. Functional analyses demonstrated that genetic knockdown of NDUFS4 impaired complex I activity, reduced mitochondrial mass, and resensitized resistant cells to olaparib. Pharmacologic targeting of NDUFS4 using the niclosamide analog ARVib-7 phenocopied genetic depletion, suppressing mitochondrial respiration and enhancing olaparib efficacy to inhibit the growth of resistant spheroids. Both NDUFS4 silencing and ARVib-7 treatment induced ferroptotic stress, as evidenced by intracellular iron accumulation and altered expression of ferroptosis-associated markers, including COX2, CHAC1, NRF2, and GPX4. These findings identify NDUFS4 as a key mediator of PARPi resistance and a therapeutic vulnerability in advanced prostate cancer. Targeting NDUFS4 disrupts OxPhos and induces ferroptosis, providing a strong rationale for combination strategies with PARPis to overcome drug resistance.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1157
Redox Biol. 2026 Apr 25. pii: S2213-2317(26)00186-2. [Epub ahead of print]94 104188

DNMT1-DUOXA1 axis discovers a novel methylation-ferroptosis circuit in bicalutamide-resistant prostate cancer.

Shunyao Xia, Yan Sun, Ziwen Ye, Haixing Jia, Zan Liu, Youcheng Xiu.

  Prostate cancer, a prevalent malignancy in the male reproductive system, poses significant therapeutic challenges due to the development of resistance to androgen deprivation therapies such as bicalutamide. While current research predominantly focuses on androgen receptor (AR)-dependent mechanisms of resistance, non-AR-dependent pathways remain poorly understood. Here, we report a novel non-AR-dependent mechanism of bicalutamide resistance centered on DUOXA1, a maturation factor for dual oxidases (DUOX) that catalyzes hydrogen peroxide (H2O2) production. Our analysis of RNA sequencing data from bicalutamide-resistant and sensitive prostate cancer cells revealed DUOXA1 as a significantly downregulated gene in resistant cells. We demonstrate that hypoxia in the prostate cancer microenvironment enhances HIF1α transcriptional activity, leading to increased DNMT1 expression. DNMT1, an epigenetic modifier, mediates the methylation of the DUOXA1 promoter, thereby silencing its expression. This epigenetic silencing of DUOXA1 inhibits ferroptosis, a form of regulated cell death characterized by iron metabolism disruption and lipid peroxidation, thereby promoting bicalutamide resistance. Our findings indicate that DUOXA1 can enhance bicalutamide resistance by promoting ferroptosis through ROS generation. This study not only provides mechanistic insights into the role of DUOXA1 in bicalutamide resistance but also highlights the HIF1α-DNMT1-DUOXA1 axis as a critical regulator of resistance. Our work suggests potential therapeutic strategies to overcome resistance through epigenetic modulation and activation of DUOXA1, offering a novel perspective on the molecular mechanisms of bicalutamide resistance and paving the way for the development of improved treatment approaches for advanced prostate cancer.

Keywords:  Bicalutamide; DUOXA1; Epigenetic modification; Ferroptosis; Prostate cancer

DOI:  https://doi.org/10.1016/j.redox.2026.104188
Endocrinology. 2026 May 05. pii: bqag056. [Epub ahead of print]

Breaking the bonds: targeting protein dimerization for prostate cancer therapy.

Nidhi Singh, Hannelore V Heemers.

  Metastatic prostate cancer (PCa) remains a major cause of cancer deaths in western men. Although androgen deprivation therapy (ADT) initially induces remissions, patients ultimately develop uncurable castration resistance, underscoring the need for alternative or complementary therapeutic strategies. Protein-protein interactions (PPIs) play a central role in oncogenic signaling, and aberrant protein dimerization is increasingly recognized as a critical driver of PCa progression and therapeutic resistance. Both homodimeric and heterodimeric protein complexes regulate key pathways involved in androgen receptor signaling, transcriptional control, and adaptation to tumor microenvironmental stress. Here, we review current evidence for oncogenic dimerization events in PCa and discuss their relevance for PCa progression. We highlight how similar dimeric interactions have been successfully targeted for therapy in other malignancies, with several strategies advancing to late-stage clinical trials or regulatory approval, underscoring their translational potential for PCa. We summarize approaches to modulate dimerization and highlight their mechanisms of action, therapeutic advantages, and inherent limitations. By combining pre-clinical and clinical findings with conceptual therapeutic frameworks, this review outlines the opportunities and limitations of targeting protein dimerization in PCa. Collectively, we propose that rational disruption of oncogenic homo- and heterodimers represents an underexplored yet promising therapeutic strategy that could complement existing treatments and help overcome resistance in advanced PCa.

Keywords:  androgen deprivation therapy; androgen receptor; castration; protein-protein interaction; targeted therapy; treatment resistance

DOI:  https://doi.org/10.1210/endocr/bqag056
J Biochem Mol Toxicol. 2026 May;40(5): e70884

Indirubin Sensitizes Prostate Cancer to Docetaxel by Inhibiting Autophagy Through the circ-Vav3/miR-204-5p/MAPK1 Pathway.

Minghao Zheng, Gan Cai, Long Ma, Xian Wu, Qian Wang, Zhenhua Jin, Chen Zhu, Shuaiyu Niu, Yanpei Peng, Yan Xu, Jingyuan Tang, Yunfei Wei.

  Accumulating evidence indicates that indirubin exerts inhibitory effects on prostate cancer (PCa) progression. However, the role and underlying mechanisms of indirubin in sensitizing PCa to docetaxel remain unclear. CCK-8 assays were initially used to determine the effect of indirubin on enhancing docetaxel sensitivity in PCa cells. Following this, the expression levels of circ-Vav3 were quantified using quantitative real-time PCR (RT-qPCR) to evaluate its potential role in docetaxel resistance. Functional experiments, including flow cytometry-based apoptosis analysis and Transwell migration/invasion assays, were conducted to assess the impact of circ-Vav3 modulation and indirubin treatment on cell viability and behavior in response to docetaxel. Rescue experiments were subsequently performed to further confirm the regulatory effect of indirubin on circ-Vav3. Additionally, xenograft tumor models in nude mice were utilized to evaluate the therapeutic efficacy of indirubin in vivo. Mechanistic interactions between circ-Vav3, miR-204-5p, and MAPK1 were further investigated using RNA pulldown assays, luciferase reporter assays, and Western blot analyses. Indirubin enhanced the sensitivity of PCa cells to docetaxel by downregulating the expression of circ-Vav3, which was found to be significantly upregulated in docetaxel-resistant PCa cells. Silencing circ-Vav3 effectively reversed this resistance, as evidenced by increased apoptosis, reduced cell migration and invasion, and decreased autophagic activity. Notably, indirubin treatment suppressed circ-Vav3 expression and thereby restored docetaxel sensitivity both in vitro and in xenograft tumor models. Mechanistically, circ-Vav3 acted as a competing endogenous RNA (ceRNA) by sponging miR-204-5p, which led to the upregulation of the autophagy-related kinase MAPK1. Inhibition of MAPK1 effectively suppressed autophagy and re-sensitized docetaxel-resistant PCa cells, further confirming the critical regulatory role of the circ-Vav3/miR-204-5p/MAPK1 signaling axis in mediating chemoresistance. Our findings demonstrate that circ-Vav3 promotes docetaxel resistance in PCa by sponging miR-204-5p and subsequently activating MAPK1-mediated autophagy. Indirubin effectively restores chemosensitivity by targeting this regulatory pathway, offering a promising therapeutic strategy for overcoming chemoresistance in castration-resistant prostate cancer (CRPC).

Keywords:  MAPK1; autophagy; circ‐Vav3; docetaxel resistance; indirubin; miR‐204‐5p; prostate cancer

DOI:  https://doi.org/10.1002/jbt.70884
Int J Biol Sci. 2026 ;22(8): 4417-4440

NLRX1 Drives Prostate Cancer Progression Through Activation of AKT and ERK Signaling Pathways.

Varsha Rathore, Ching-Yuan Cheng, Duen-Yi Huang, Shao-Peng Chen, Liang Huan Wu, Jitendra Maharana, Chuang-Rung Chang, Wan-Wan Lin.

  NLRX1, a mitochondrial NOD-like receptor (NLR) family protein, is a non-inflammasome-forming protein with diverse roles in cancer. While NLRX1 has been recognized as a tumor suppressor in colorectal and hepatocellular carcinomas, it appears to act as a tumor promoter in breast and head and neck cancers. This study explored the role of NLRX1 in prostate cancer (PCa), examining its impact on cell proliferation, apoptosis, migration, invasion, and tumor progression, as well as associated molecular mechanisms. Using TCGA data, the association between NLRX1 expression and PCa prognosis was evaluated. NLRX1 expression was upregulated under serum-free stress conditions. Silencing NLRX1 reduced cell proliferation in PC3 cells, but not in LNCaP cells. Additionally, NLRX1 knockdown inhibited migration and invasion, while promoting apoptosis under serum-free conditions. Mechanistically, NLRX1 knockdown reduced AKT and ERK phosphorylation in response to serum deprivation, EGF, and TGF-β, without affecting PDK1 activity under serum deprivation. Pharmacological data showed AKT and ERK as key regulators of viability and invasion, with AKT critical for growth and migration. Co-immunoprecipitation, confocal microscopic examination, domain binding, structural modeling, and molecular dynamics revealed a stable interaction between NLRX1's LRR domain and AKT's PH domain. NLRX1 facilitated cell proliferation, migration, invasion, and resistance to serum-free stress through direct interaction with AKT, highlighting NLRX1 as a promising biomarker for PCa progression.

Keywords:  AKT; Apoptosis; Invasion; Migration; NLRX1; Prostate cancer

DOI:  https://doi.org/10.7150/ijbs.126054