Song Feifeng, Zhang Qi, Zhang Zhentao, Xu Tong, Qin Hui, Lou Yutao, Zhang Wanli, Liu Feng, Zhang Yiwen, Huang Ping
Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China.
Zhejiang Provincial Clinical Research Center for Malignant Tumor, Hangzhou, China.
FASEB J. 2025 Jun 30;39(12):e70727. doi: 10.1096/fj.202500857R.
The poor prognosis of clear cell renal cell carcinoma (ccRCC) is primarily attributed to inherent resistance and malignant progression, yet the underlying mechanism and effective strategies remain poorly understood. Renal drug transporters play an indispensable role in regulating the intracellular concentration of tumor cells. Therefore, this study aims to investigate the role of proton-coupled oligopeptide transporter 2 (PEPT2) in ccRCC. PEPT2 was found to be downregulated in ccRCC tissues and cell lines, and its low expression was associated with an unfavorable prognosis in ccRCC patients. Overexpression of PEPT2 inhibited cell proliferation and metastasis both in vitro and in vivo. Furthermore, the transcriptional repression of PEPT2 was attributed to DNMT3A/B mediated methylation of its promoter, which could be reversed by the epigenetic inhibitor decitabine, leading to the restored expression and functional transport activity of PEPT2. Importantly, the combination treatment with decitabine (an epigenetic inhibitor) and a lenalidomide-dipeptide conjugate (a substrate for PEPT2) significantly enhanced cytotoxicity against ccRCC cells both in vitro and in vivo. Our investigation into the epigenetic repression of PEPT2 promoters has revealed a significant role in the progression of ccRCC. Furthermore, our findings demonstrate that the combination of PEPT2-targeted lenalidomide with epigenetic therapy effectively enhances cytotoxicity in ccRCC cells. This study provides compelling experimental evidence for the potential therapeutic benefit of targeting PEPT2 in the treatment of ccRCC.
透明细胞肾细胞癌（ccRCC）预后较差，主要归因于其内在抗性和恶性进展，但其潜在机制和有效策略仍知之甚少。肾脏药物转运体在调节肿瘤细胞内药物浓度方面发挥着不可或缺的作用。因此，本研究旨在探讨质子偶联寡肽转运体2（PEPT2）在ccRCC中的作用。研究发现，PEPT2在ccRCC组织和细胞系中表达下调，其低表达与ccRCC患者预后不良相关。PEPT2过表达在体外和体内均抑制细胞增殖和转移。此外，PEPT2的转录抑制归因于DNMT3A/B介导的其启动子甲基化，表观遗传抑制剂地西他滨可逆转这种甲基化，从而使PEPT2的表达和功能性转运活性得以恢复。重要的是，地西他滨（一种表观遗传抑制剂）与来那度胺 - 二肽缀合物（PEPT2的底物）联合治疗在体外和体内均显著增强了对ccRCC细胞的细胞毒性。我们对PEPT2启动子表观遗传抑制的研究揭示了其在ccRCC进展中的重要作用。此外，我们的研究结果表明，靶向PEPT2的来那度胺与表观遗传疗法联合可有效增强对ccRCC细胞的细胞毒性。本研究为靶向PEPT2治疗ccRCC的潜在治疗益处提供了有力的实验证据。
