Gao Rui, Liu Zixue, Meng Mei, Song Xuefei, He Jian
State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Pharmaceuticals (Basel). 2024 Mar 30;17(4):451. doi: 10.3390/ph17040451.
The transketolase 1 gene (TKTL1) is an essential factor that contributes to brain development. Some studies have shown the influence of TKTL1 in cancers, but it has been rarely reported in kidney cancer. Furthermore, the role of TKTL1 in the prognosis and tumor infiltration of immune cells in various cancers, particularly kidney cancer, remains unknown. In this study, TKTL1 expression and its clinical characteristics were investigated using a variety of databases. TIMER was used to investigate the relationship between TKTL1 and immune infiltrates in various types of cancer. We also studied the relationship between TKTL1 expression and response to PD-1 blocker immunotherapy in renal cancer. We conducted TKTL1 agonists virtual screening from 13,633 natural compounds (L6020), implemented secondary library construction according to the types of top results, and then conducted secondary virtual screening for 367 alkaloids. Finally, in vitro assays of cell viability assays and colony formation assays were performed to demonstrate the pharmacological potency of the screening of TKTL1 agonists. Using these methods, we determined that TKTL1 significantly affects the prognostic potential in different types of kidney cancer patients. The underlying mechanism might be that the TKTL1 expression level was positively associated with devious immunocytes in kidney renal clear cell carcinoma (KIRC) rather than in kidney renal papillary cell carcinoma (KIRP) and kidney chromophobe (KICH). This recruitment may result from the up-regulation of the mTOR signaling pathway affecting T cell metabolism. We also found that TKTL1 may act as an immunomodulator in KIRC patients' response to anti-PD-1 therapy. Moreover, we also found that piperine and glibenclamide are potent agonists of TKTL1. We have demonstrated, in vitro, that piperine and glibenclamide can inhibit the proliferation and clone formation of Caki-2 cell lines by agonizing the expression of TKTL1. In summary, our discovery implies that TKTL1 may be a promising prognostic biomarker for KIRC patients who respond to anti-PD-1 therapy. Piperine and glibenclamide may be effective therapeutic TKTL1 agonists, providing a theoretical basis for the clinical treatment of kidney cancer.
转酮醇酶1基因（TKTL1）是促进大脑发育的一个重要因素。一些研究显示了TKTL1在癌症中的影响，但在肾癌中的报道很少。此外，TKTL1在各种癌症，尤其是肾癌的预后及免疫细胞肿瘤浸润中的作用仍不清楚。在本研究中，利用各种数据库对TKTL1表达及其临床特征进行了研究。使用TIMER来研究TKTL1与各种癌症中免疫浸润的关系。我们还研究了TKTL1表达与肾癌中对PD-1阻断剂免疫治疗反应的关系。我们从13633种天然化合物（L6020）中进行TKTL1激动剂虚拟筛选，根据顶级结果的类型进行二级文库构建，然后对367种生物碱进行二级虚拟筛选。最后，进行细胞活力测定和集落形成测定的体外试验，以证明TKTL1激动剂筛选的药理效力。通过这些方法，我们确定TKTL1显著影响不同类型肾癌患者的预后潜力。潜在机制可能是TKTL1表达水平与肾透明细胞癌（KIRC）而非肾乳头状细胞癌（KIRP）和肾嫌色细胞癌（KICH）中的迂回免疫细胞呈正相关。这种募集可能是由于影响T细胞代谢的mTOR信号通路的上调所致。我们还发现TKTL1可能在KIRC患者对抗PD-1治疗的反应中充当免疫调节剂。此外，我们还发现胡椒碱和格列本脲是TKTL1的有效激动剂。我们在体外证明，胡椒碱和格列本脲可通过激动TKTL1的表达来抑制Caki-2细胞系的增殖和克隆形成。总之，我们的发现表明，TKTL1可能是对抗PD-1治疗有反应的KIRC患者的一个有前景的预后生物标志物。胡椒碱和格列本脲可能是有效的治疗性TKTL1激动剂，为肾癌的临床治疗提供了理论依据。
