Abstract Metastatic castration-resistant prostate cancer (mCRPC) represents the most advanced stage of the disease, with no curative treatments. lncRNAs are emerging regulators of prostate cancer (PCa) biology and the lncRNA PCGEM1 has been linked to tumorigenesis and c-Myc activity in AR positive cells, but its role in an androgen independent context is less characterized. PCGEM1 expression across ISUP grades was assessed by linear trend testing, and its association with progression-free survival was evaluated by Kaplan-Meier analysis in the TCGA-PRAD cohort. PC3 cells were transfected with a PCGEM1 expression plasmid or empty vector and validation by qPCR and MTS assays were performed at 24, 48 and 72 h. Clonogenic, hanging drop, and wound healing assays were conducted at 72h. To assess cell morphology, DAPI/phalloidin staining and fluorescence microscopy were performed. ER-stress and EMT programs were examined by RT-qPCR. Proteomic profiling of PC3 transfected cells was performed by LC-ESI-MS/MS followed by GSEA analysis, and pathway enrichment patterns were further evaluated in the MD Anderson PDX and SU2C cohorts. PCGEM1 expression declined with increasing ISUP grade, and higher levels correlated with longer progression-free survival in the TCGA-PRAD cohort. In PC3 cells, PCGEM1 overexpression reduced cell viability at 72 h, markedly impaired clonogenic growth, and decreased spheroid size. Transfected cells displayed an elongated morphology with increased cell area and reduced circularity, but both CDH1 and CDH2 expression were reduced whereas FN1 and TWIST1 had no changes. Furthermore, PC3-overexpressing cells had migration impaired at all times assessed (3, 6 and 24 h). ER-stress markers (HSPA5, XBP1, DDIT3) were upregulated, indicating activation of stress-response pathways. Proteomic analysis of PC3 transfected cells with PCGEM1 revealed repression of translational and ribosomal-biogenesis programs and downregulation of MYC-target pathways. Finally, the evaluation of MYC-core proteins in PDX models segregated AR-positive adenocarcinomas from poorly differentiated or AR-low tumors, whereas clustering in the SU2C cohort was more heterogeneous. PCGEM1 is reviewed in literature as an oncogenic lncRNA and its overexpression in AR-positive PCa cells is associated with a more aggressive phenotype. Nevertheless, its overexpression in an androgen-independent context induced ER-stress programs, suppressed protein biosynthetic and MYC-related pathways, and impaired key malignant traits. This response suggests that excessive PCGEM1 activation becomes incompatible with cellular homeostasis, inducing a hyperactivation-induced lethality mechanism. These findings highlight a previously unrecognized regulatory role for PCGEM1 and suggest that exploiting lncRNA hyperactivation may uncover a therapeutic vulnerability in advanced, therapy-refractory PCa. Citation Format: Sabrina Ledesma-Bazan, Pablo Sanchis, Rocio Seniuk, Gaston Pascual, María Jimena Rada, Manuel Agulleiro, Camila Russo, Pia Valacco, Elba Vazquez, Geraldine Gueron, Javier Cotignola. PCGEM1 overload: Triggering lethal stress responses in castration-resistant prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5908.
Ledesma-Bazan et al. (Fri,) studied this question.