bims-meproc 2025-06-01 papers

Issue of 2025–06–01
seven papers selected by
Grigor Varuzhanyan, UCLA

Discov Oncol. 2025 May 30. 16(1): 967

NEIL3 promotes the carcinogenesis of prostate cancer by activating PI3K/Akt/mTOR signaling.

Wei Zhang, Zihao Liu, Simeng Wen, Yuan Shao, Zhen Yang, Yong Wang.

Prostate cancer (PCa) is one of the most common cancers worldwide. Nei endonuclease VIII-like 3 (NEIL3) plays important roles in diverse cancers. In this study, we found that NEIL3 was overexpressed in PCa tissues and cell lines. NEIL3 over-expression was associated with worse prognostic outcomes in PCa patients. In vitro, PCa cell proliferation, invasion, and migration could be significantly inhibited with knocking down NEIL3 by inactivating the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) signaling. Besides, we found that the expression of high-mobility gene group A2 and androgen receptor (AR) were upregulated in PCa tissues, and their expression was decreased in C4-2 cells treated with siNEIL3. Nevertheless, R1881 could enhance si-NEIL3-inhibited PI3K, AKT and mTOR phosphorylation levels in both C4-2 cells and PC-3M. In conclusion, NEIL3 could promote the progression of PCa by activating PI3K/AKT/mTOR signaling in PCa cells. Therefore, these results may provide a potential molecular target for PCa treatment.

Keywords: AR; HMGA2; NEIL3; PI3K; Prostate cancer

DOI: https://doi.org/10.1007/s12672-025-02625-w

Mol Cell Biochem. 2025 May 28.

GPR55 senses lactate to sustain motility in prostate cancer cells.

Giovanna Sgrignani, Marta Iozzo, Lara Di Leonardo, Elisa Pardella, Erica Pranzini, Giulia Gangarossa, Giuseppina Comito, Luigi Ippolito, Elisa Giannoni, Paola Chiarugi.

The enrichment of specific metabolites within the tumor microenvironment is emerging as a driver of tumor progression. Specifically, in prostate cancer (PCa), increased abundance of lactate is associated with primary-to-metastasis tumor spreading by supporting cancer cell invasiveness. Here, we highlight that the endocannabinoid receptor GPR55 is able to sense lactate and consequently trigger PCa cell amoeboid-like invasiveness, through the activation of the pro-migratory RhoA/MLC2 signaling pathway. These findings uncover a new role for GPR55 in sustaining lactate-driven PCa cell motility.

Keywords: Amoeboid motility; GPR55; Lactate; Prostate cancer

DOI: https://doi.org/10.1007/s11010-025-05312-0

Biology (Basel). 2025 May 06. pii: 507. [Epub ahead of print]14(5):

Targeting Methionine Metabolism Reveals AMPK-SAMTOR Signaling as a Therapeutic Vulnerability in Prostate Cancer.

Serdar Arisan, Ayyuce Sever, Pinar Obakan-Yerlikaya, Elif Damla Arisan, Pinar Uysal-Onganer.

Prostate cancer (PCa) is not only one of the most diagnosed malignancies in men but also a leading cause of cancer-related mortality globally. PCa exhibits unique metabolic dependencies, particularly on lipids and glutamine, unlike many solid tumors, rather than glycolysis. Methionine metabolism plays a crucial role in these metabolic pathways, contributing to polyamine biosynthesis, DNA methylation, and cellular signaling processes. Here, we demonstrate that methionine deprivation induces selective vulnerability in AMPK-deficient PC3 PCa cells by disrupting SAMTOR-mTOR signaling and triggering oxidative stress, lipid depletion, and autophagic responses. Through functional and proteomic analyses, we show that SAMTOR directly interacts with p-AMPK and modulates cell fate under methionine-limited conditions. Our findings establish a mechanistic link between methionine sensing and metabolic stress signaling in PCa, offering a new avenue for targeted intervention.

Keywords: SAMTOR; autophagy; mTOR; methionine; prostate cancer

DOI: https://doi.org/10.3390/biology14050507

Int J Mol Sci. 2025 May 20. pii: 4883. [Epub ahead of print]26(10):

Gα13 Promotes Clonogenic Growth by Increasing Tolerance to Oxidative Metabolic Stress in Prostate Cancer Cells.

Di Wu, Wei Kiang Lim, Xiaoran Chai, Veerabrahma Pratap Seshachalam, Suhail Ahmed Kabeer Rasheed, Sujoy Ghosh, Patrick J Casey.

The oncogenic role of the G12 family in many human solid cancers has been extensively studied, primarily through the effects of constitutively active mutants of these proteins on cell migration and invasion. However, these mutations are not seen in cancers, and the biological role of Gα13 in prostate cancer tumorigenesis is largely unexplored. Here, we report that Gα13 promotes anchorage-independent colony formation, spheroid formation, and xenograft tumor growth in human prostate cancer cell lines. Transcriptome analyses suggest that Gα13 modulates genes in the mitochondria and are involved in the oxidative stress response. Silencing of GNA13 increased mitochondrial superoxide levels when prostate cancer cells were cultured in galactose medium and increased the sensitivity to oxidative metabolic stress when the cells were cultured in media containing non-glycolytic metabolites. Furthermore, Gα13 levels impacts the abundance of superoxide dismutase 2 (SOD2) in the mitochondria, as well as SOD2 promoter activity and mRNA expression. Importantly, expression of SOD2 could rescue the effect of Gα13 loss on suppression of anchorage-independent growth. Likewise, stable knockdown of SOD2 decreased anchorage-independent cell growth, which was enhanced by overexpression of Gα13. These results outline a novel biological function of Gα13 mediated via SOD2 in prostate cancer tumorigenesis and highlight it as a potential treatment target.

Keywords: GNA13; Gα13; LNCaP; PC3; SOD2; mitochondria; oxidative metabolic stress; prostate cancer; superoxide; superoxide dismutase

DOI: https://doi.org/10.3390/ijms26104883

Chin Med. 2025 May 26. 20(1): 71

Evodiamine induces ferroptosis in prostate cancer cells by inhibiting TRIM26-mediated stabilization of GPX4.

Lanlan Li, Jianzhong Lu, Shengjun Fu, Wenyan Li, Ying Wang, Ke Wang, Yan Tao, Shanhui Liu.

BACKGROUND: Prostate cancer is a major global health challenge, characterized by high morbidity and mortality rates. Traditional treatment options, including androgen deprivation therapy and chemotherapy, often lead to drug resistance. In recent years, natural compounds have garnered attention for their potential therapeutic effects. Evodiamine, a bioactive alkaloid from Evodia rutaecarpa, has demonstrated promising anti-cancer properties in various malignancies, including oral squamous cell carcinoma, breast, colorectal, and ovarian cancers. This study explores the efficacy of evodiamine in prostate cancer cells and investigates the mechanisms underlying evodiamine-induced cell death.
METHODS: To investigate the effects of evodiamine on prostate cancer cells, various cell lines, including both castration-sensitive and castration-resistant variants, were treated with different concentrations of evodiamine for various durations. Cell viability, proliferation, invasion ability, and colony formation were assessed using the CCK8 assay, EdU assay, 3D matrigel drop invasion assay, and colony formation assay, respectively. The effects of evodiamine on apoptosis were analyzed using FACS, Hoechst staining, and Western blot. To evaluate its effects on ferroptosis, malondialdehyde (MDA) and glutathione (GSH) assay kits, as well as DCFH-DA and the lipid peroxidation sensor BODIPY™ 581/501 C11 fluorescent probes, were employed. The molecular mechanisms through which evodiamine regulates GPX4 protein instability were investigated using Western blot and TRIM26 ectopic expression. Additionally, a mouse xenograft model derived from DU145 cells was established to evaluate the in vivo effects of evodiamine and its molecular mechanisms, utilizing hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and Western blot analysis.
RESULTS: Evodiamine significantly suppressed cell viability, proliferation, invasion, and colony formation in prostate cancer cells. Importantly, evodiamine-induced cell death in the PC3 and DU145 cell lines was independent of apoptosis pathway. Instead, evodiamine increased reactive oxygen species (ROS) production, lipid ROS levels and MDA levels, while decreasing GSH levels, indicating the induction of ferroptosis. The key role of ROS in evodiamine-induced ferroptosis was further confirmed by the partial reversal of cell death upon treatment with the ROS scavenger N-acetylcysteine (NAC). Mechanistically, evodiamine induced ferroptosis by destabilizing GPX4 protein in a TRIM26-dependent manner. Moreover, in vivo studies demonstrated that evodiamine significantly inhibited tumor growth and induced ferroptosis in tumor cells, highlighting its therapeutic potential.
CONCLUSION: This study demonstrates that evodiamine exerts potent antitumor effects against prostate cancer through inhibiting TRIM26-mediated stabilization of GPX4 protein and triggering ferroptosis. These findings suggest that evodiamine, a natural product derived from traditional Chinese medicine, could be a promising therapeutic agent for prostate cancer.

Keywords: Evodiamine; Ferroptosis; GPX4; Prostate cancer; TRIM26

DOI: https://doi.org/10.1186/s13020-025-01130-0

Cancers (Basel). 2025 May 09. pii: 1610. [Epub ahead of print]17(10):

PI3Kδ as a Novel Therapeutic Target for Aggressive Prostate Cancer.

Bi-Dar Wang, Alyssa Lucero, Siyoung Ha, Reyhaneh Yarmohammadi.

Phosphoinositide 3-kinases (PI3Ks) signaling represents an important pathway regulating cell proliferation, survival, invasion, migration, and metabolism. Notably, PI3K/AKT/mTOR signaling is frequently dysregulated in the majority of malignancies. Among the class IA PI3Ks (PI3Kα/β/δ), emerging evidence has implicated that PI3Kδ is not only overexpressed in leukocytes but also in solid tumors, including prostate cancer. The critical role of PI3Kδ in tumorigenesis and in the creation of a suppressive tumor microenvironment, along with the recent finding of PI3Kδ splice isoforms in promoting tumor aggressiveness and resistance, further demonstrates the potential of developing novel PI3Kδ-targeted cancer therapies. In this review, we comprehensively describe the functional mechanisms underlying the PI3Kδ-driven tumor progression and immune regulation in prostate cancer diseases. Furthermore, the recent preclinical and clinical studies on the development of PI3Kδ-/PI3K-targeted inhibitors as single agents and in combination therapies (with chemotherapy, radiation, hormone therapy, or immunotherapy) are summarized. Finally, we discuss the potential novel therapies for improving the treatment efficacies, as well as the current limitations and challenges of PI3Kδ-based therapies for prostate cancer.

Keywords: PI3K/AKT/mTOR signaling; PI3Kδ and pan-PI3K inhibitors; androgen receptor inhibitors; combination therapies; immune checkpoint blockers; phosphoinositide 3-kinases delta (PI3Kδ); splice isoforms; tumor immune microenvironment

DOI: https://doi.org/10.3390/cancers17101610

Biochim Biophys Acta Gen Subj. 2025 May 28. pii: S0304-4165(25)00073-X. [Epub ahead of print] 130828

Ferroptosis induction, androgen biosynthesis disruption and prostate cancer suppression by androgen and vitamin D combination.

Bobae Park, Subash Khadka, Jungmi Ahn, Jacqueline Vaquiz, Okunola Igbekoyi, Chung S Song, Bandana Chatterjee.

Prostate cancer regression by hormonal vitamin D3(calcitriol) is clinicallyuntenable despite its well-documented anticancer effects in experimental models, sincesupraphysiologic dosing of calcitriolrequiredin clinical settings causes hypercalcemia and other toxicities. We show that subnanomolar/low-nanomolar calcitriol, while non-inhibitory on its own, inhibited CRPC cells upon co-treatment with androgen (5α-DHT) ata physiologic level, evidentfrom G1/S cell cycle arrest, induction of p21/Cip1, blockade of clonal cell growth, retardation of proliferation, migration and invasion of cellsinvitro, and xenograft growth suppressioninvivo. AKR1D1, an androgen-inactivating 5β-reductase, was upregulated >30-fold upon calcitriol/DHT co-treatment, while each hormone individually didnot induce AKR1D1. In contrast, HSD3β1, a key enzyme for androgen biosynthesis, was upregulated >12-fold by calcitriol, which was blocked by DHT co-treatment. Elevated AKR1D1 and reducedHSD3β1 wouldlower intracellular androgens and contribute to CRPC repression.Autophagy mediated ferroptosis (ferritinophagy) paralleled CRPC growth inhibition by the hormone combination -indicated by LC3B induction, ferritin reduction, and upregulation of mRNAs encodingNCOA4, ALOX-5 and PTGS2which arecore participants in ferroptosis.The combination treatment caused lipid peroxidation, evident from thefluorescence shift of C11-BODIPY(581/591)-labeled cells from red to green, and from elevated malondialdehyde. GPX4 - an antioxidant peroxidase and ferroptosis regulator - was downregulated.Bipolar androgen therapy employing supraphysiologic testosterone isunderclinical evaluation for efficacy against treatment-resistant metastatic CRPC, although the high androgen dose raises safety concerns. Vitamin D and androgen administered concurrently at physiologic levels may offer a superior alternativefor arresting CRPC.

Keywords: Androgen; Androgen inactivation; Combination treatment; Ferritinophagy; Lipid peroxidation; Prostate cancer; Vitamin D

DOI: https://doi.org/10.1016/j.bbagen.2025.130828