Zheng Bin, Liu Kan, Feng Ji, Ouyang Qing, Jia Tongyu, Wang Yaohui, Tian Shuo, Chen Xinran, Cai Tianwei, Wen Lequan, Zhang Xu, Li Xiubin, Ma Xin
Medical School of Chinese PLA, Beijing, 100853, China.
Department of Urology, The Third Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China.
Biol Direct. 2025 Apr 2;20(1):43. doi: 10.1186/s13062-025-00641-y.
Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC. Even though the targeted drugs for the treatment of ccRCC have a certain therapeutic effect, due to the problem of drug resistance, the search for new targets for targeted therapy of ccRCC remains urgent. GAMT is an enzyme involved in creatine metabolism. However, the precise biological roles and molecular mechanisms of GAMT in ccRCC are not fully understood.
Here, we found that GAMT was upregulated in ccRCC cells and tissues and associated with poor prognosis. Further, GAMT has pro-oncogenic abilities in promoting ccRCC development and progression. Intriguingly, GAMT exerted biological functions independent of its role in catalyzing creatine synthesis. Mechanistically, GAMT overexpression contributes to the development and progression of ccRCC by inhibiting tumor suppressor p53. Finally, we identified fisetin as a novel GAMT inhibitor and validated its role in suppressing ccRCC progression and sensitizing ccRCC cells to targeted drug axitinib via in vivo and in vitro assays.
This study reveals that GAMT has pro-oncogenic abilities in promoting ccRCC development and progression. GAMT exerted its non-enzymatic functions possibly by regulating the expression of p53. Fisetin, the novel GAMT inhibitor identified herein, may serve as a new antitumor drug for ccRCC treatment.
透明细胞肾细胞癌（ccRCC）是肾细胞癌最常见的类型。尽管用于治疗ccRCC的靶向药物具有一定的治疗效果，但由于耐药性问题，寻找ccRCC靶向治疗的新靶点仍然十分迫切。胍氨酸甲基转移酶（GAMT）是一种参与肌酸代谢的酶。然而，GAMT在ccRCC中的确切生物学作用和分子机制尚未完全明确。
在此，我们发现GAMT在ccRCC细胞和组织中上调，并与不良预后相关。此外，GAMT在促进ccRCC发展和进展方面具有促癌能力。有趣的是，GAMT发挥生物学功能与其在催化肌酸合成中的作用无关。机制上，GAMT过表达通过抑制肿瘤抑制因子p53促进ccRCC的发展和进展。最后，我们鉴定出非瑟酮作为一种新型GAMT抑制剂，并通过体内和体外实验验证了其在抑制ccRCC进展以及使ccRCC细胞对靶向药物阿西替尼敏感方面的作用。
本研究表明GAMT在促进ccRCC发展和进展方面具有促癌能力。GAMT可能通过调节p53的表达发挥其非酶促功能。本文鉴定出的新型GAMT抑制剂非瑟酮可能作为一种新的抗肿瘤药物用于ccRCC治疗。
