Wu Chia-Chang, Hu Su-Wei, Dong Shao-Wei, Tzou Kai-Yi, Li Chien Hsiu
Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Taipei Medical University (TMU) Research Center of Urology and Kidney, Taipei Medical University, Taipei City, Taiwan.
Geroscience. 2025 Jan 31. doi: 10.1007/s11357-025-01538-4.
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.
溶质调节异常与癌症进展相关，相关载体是预后和治疗的潜在靶点。雄激素剥夺疗法（ADT）对前列腺癌（PCa）进展至关重要，但继发性耐药常导致雄激素非依赖性肿瘤生长，因此需要新的预后生物标志物。基于转录组的数据集确定精氨酸载体SLC25A29在PCa中上调，与转移特征相关，并作为高危预后因素，特别是在去势抵抗性前列腺癌（CRPC）中。分子模拟表明，SLC25A29介导的途径有助于线粒体代谢和氧化还原稳态，涉及POLD1调节并提示与铁死亡有关。进一步分析表明，SLC25A29可能通过E2F1反式激活POLD1，CRPC相关细胞中E2F1敲低的RNA测序分析表明，POLD1表达降低。临床和细胞研究证实，SLC25A29、E2F1和POLD1水平与病理特征呈正相关，其下游效应物可作为预后标志物。SLC25A29/E2F1/POLD1轴与神经内分泌PCa（NEPC）的发生相关，表明其在雄激素受体抑制反应中的作用。E2F1的下调不仅降低了POLD1水平，还减少了NEPC相关标志物。这些发现支持SLC25A29/E2F1/POLD1轴作为CRPC和NEPC的预后工具，靶向E2F1可能提供一种破坏SLC25A29介导的PCa进展的治疗策略。
