The prognostic and neuroendocrine implications of SLC25A29-mediated biomass signature in prostate cancer

Abstract

Dysregulated solutes are linked to cancer progression, with associated carriers being potential targets for prognosis and treatment. Androgen deprivation therapy (ADT) is essential for prostate cancer (PCa) progression, but secondary resistance often leads to androgen-independent tumor growth, necessitating new prognostic biomarkers. Transcriptome-based datasets identify SLC25A29, an arginine carrier, as upregulated in PCa, correlating with metastatic features and serving as a high-risk prognostic factor, particularly in castration-resistant prostate cancer (CRPC). Molecular simulations indicate that SLC25A29-mediated pathways contribute to mitochondrial metabolism and redox homeostasis, implicating POLD1 regulation and suggesting a link to ferroptosis. Further analysis reveals that SLC25A29 may transactivate POLD1 via E2F1, as shown by RNA-seq profiling of E2F1 knockdown in CRPC-related cells, which demonstrated reduced POLD1 expression. Clinical and cellular studies confirm that SLC25A29, E2F1, and POLD1 levels positively correlate with pathological features, with their downstream effectors serving as prognosis signatures. The SLC25A29/E2F1/POLD1 axis is associated with neuroendocrine PCa (NEPC) development, indicating its role in response to androgen receptor inhibition. Downregulation of E2F1 not only decreases POLD1 levels but also reduces NEPC-related markers. These findings support the SLC25A29/E2F1/POLD1 axis as a prognostic tool for CRPC and NEPC, and targeting E2F1 may offer a therapeutic strategy to disrupt SLC25A29-mediated PCa progression.

Graphical Abstract

Through systematic bioinformatic analysis and molecular simulation models, this study elucidates the molecular mechanisms underlying prostate cancer’s tolerance to androgen deprivation therapy (ADT). Our findings propose that the upregulation of SLC25A29 leads to the transactivation of POLD1 via E2F1. This pathway mitigates redox stress and maintains mitochondrial function, thereby contributing to the progression of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). The axis involving SLC25A29, E2F1, and POLD1 emerges as a promising prognostic signature in prostate cancer.