bims-meproc 2025-04-13 papers

Issue of 2025–04–13
three papers selected by
Grigor Varuzhanyan, UCLA

bioRxiv. 2025 Mar 29. pii: 2025.03.25.645248. [Epub ahead of print]

Wnt/Beta-Catenin Signaling Is Active in Neuroendocrine Prostate Cancer.

Yingli Shi, Shu Yang, Lin Li, Siyuan Cheng, Jeyaluxmy Sivalingam, Elahe Mahdavian, Xiuping Yu.

Wnt/beta-Catenin signaling plays a critical role in prostate cancer (PCa) progression, yet its precise contributions in neuroendocrine prostate cancer (NEPCa) remain incompletely understood. In this study, we utilized TRAMP/Wnt-reporter mice to monitor Wnt/beta-Catenin activity and investigated transcriptional alterations associated with NEPCa development. RNA sequencing and pathway enrichment analyses identified neuroactive ligand-receptor interaction, MAPK, calcium, and cAMP signaling as key pathways enriched in NEPCa. Although Wnt signaling was not among the top-enriched pathways, elevated Axin2 expression and increased Wnt-reporter activity suggest its involvement in NEPCa progression. We observed upregulated expression of Wnt3, Wnt6, Dvl2, Dvl3, and Lef1 in NEPCa, coupled with reduced expression of Yap1 and Frat1, which are involved in beta-Catenin degradation. Pharmacological inhibition of Wnt/beta-Catenin signaling using FC101 significantly suppressed PCa growth, underscoring its potential as a therapeutic target. These findings reveal that Wnt/beta-Catenin signaling is active in NEPCa through multiple mechanisms and highlight the need for further investigation into the regulatory interplay between Wnt and YAP1 in prostate cancer.

DOI: https://doi.org/10.1101/2025.03.25.645248

J Biol Chem. 2025 Apr 02. pii: S0021-9258(25)00322-9. [Epub ahead of print] 108473

Tissue Inhibitor of Metalloproteinase 1 promotes ferroptosis and suppresses prostate cancer metastasis.

Yuliang Rao, Qi Pan, Siyu Liu, Shunheng Yao, Lei Li, Jianyan Yan, Lifen Chen, Li Xu, Han Yan, Aicui Ma, Fen Wang, Xiaoyan Mao, Zhonghui Wang, Junfang Zhang, Jun Guo, Zuyue Sun.

Tissue inhibitor of metalloproteinase 1 (TIMP1) has been implicated in prostate cancer metastasis. In this study, PC-3M-2B4 cells with TIMP1 knockdown (PC-3M-2B4-shTIMP1) or over-expression (PC-3M-2B4-TIMP1) were generated and an inverse correlation was found between TIMP1 expression and cell migration and invasion which was confirmed in vitro and in vivo. Differential TIMP1 expression was accompanied by variations in the expression of the ferroptosis-related proteins, glutathione peroxidase 4 (GPX4), transferrin receptor (TFRC), transferrin (TF), glutamine cysteine ligase catalytic subunit (GCLC) and glutamine cysteine ligase modifier subunit (GCLM). In comparison with TIMP1-overexpressing cells, TIMP1-knockdown cells demonstrated a 12.3% decrease in Fe2+ concentration after erastin treatment, a 37.8% reduction in malondialdehyde (MDA) levels, an 113.7% increase in GPX4 expression, and a 78.9% rise in the GSH/GSSG ratio. Our findings indicate that TIMP1 overexpression promotes ferroptosis by modulating critical markers such as GPX4 and TFRC, thereby significantly reducing metastatic potential in prostate cancer cells. Our results highlight TIMP1's role in regulating ferroptosis pathways, which are crucial for tumor progression, and exposes a potential therapeutic target for prostate cancer management.

Keywords: Ferroptosis; GPX4; Metastasis; Prostate Cancer; TIMP1

DOI: https://doi.org/10.1016/j.jbc.2025.108473

Cells. 2025 Apr 04. pii: 547. [Epub ahead of print]14(7):

The Ceramide-Dependent EV Secretome Differentially Affects Prostate Cancer Cell Migration.

Dolma Choezom, Jan-Moritz Plum, Pradhipa Karuna M, Adi Danieli-Mackay, Christof Lenz, Phillipp Brockmeyer, Julia Christina Gross.

Tumor-derived extracellular vesicles (EVs) play an important role in cancer progression. Neutral sphingomyelinases (nSMases) are lipid-modifying enzymes that modulate the secretion of EVs from cells. How nSMase activity and therefore ceramide generation affect the composition and functionality of secreted EVs is not fully understood. Here, we aimed to investigate the expression of nSMases 1 and 2 in prostate cancer (PCa) tissue and their role in EV composition and secretion for prostate cancer cell migration. Reduced nSMase 1 and 2 expression was found in prostate cancer and correlated with the age of the patient. When nSMase 2 was inhibited by GW4869 in PCa cells (PC3 and DU145), the EV secretome was significantly altered, while the number of EVs and the total protein content of released EVs were not significantly changed. Using proteomic analysis, we found that extracellular matrix proteins, such as SDC4 (Syndecan-4) and SRPX-2, were differentially secreted on EVs from GW4869-treated PC3 cells. In scratch wound migration assays, GW4869 significantly increased migration compared to control PC3 cells but not DU145 cells, while SDC4 knockdown significantly reduced the migration of PC3 cells. These and other nSMase-2-dependent secreted proteins are interesting candidates for understanding the role of stress-induced EVs in the progression of prostate cancer.

Keywords: SMPD2; SMPD3; cell migration; extracellular matrix; neutral sphingomyelinases

DOI: https://doi.org/10.3390/cells14070547