Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning 110122, China; The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, Shenyang, Liaoning 110122, China; Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China.
Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning 110122, China; Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
Sci Total Environ. 2024 Oct 15;947:174538. doi: 10.1016/j.scitotenv.2024.174538. Epub 2024 Jul 6.
Arsenic (As) is recognized as a potent environmental contaminant associated with bladder carcinogenesis. However, its molecular mechanism remains unclear. Metabolic reprogramming is one of the hallmarks of cancer and is as a central feature of malignancy. Here, we performed the study of cross-talk between the mammalian target of rapamycin complex 1 (mTORC1)/ Hypoxia-inducible factor 1 alpha (HIF-1α) pathway and aerobic glycolysis in promoting the proliferation and migration of bladder epithelial cells treated by arsenic in vivo and in vitro. We demonstrated that arsenite promoted N-methyl-N-nitrosourea (MNU)-induced tumor formation in the bladder of rats and the malignant behavior of human ureteral epithelial (SV-HUC-1) cell. We found that arsenite positively regulated the mTORC1/HIF-1α pathway through glucose transporter protein 1 (GLUT1), which involved in the malignant progression of bladder epithelial cells relying on glycolysis. In addition, pyruvate kinase M2 (PKM2) increased by arsenite reduced the protein expressions of succinate dehydrogenase (SDH) and fumarate hydratase (FH), leading to the accumulation of tumor metabolites of succinate and fumarate. Moreover, heat shock protein (HSP)90, functioning as a chaperone protein, stabilized PKM2 and thereby regulated the proliferation and aerobic glycolysis in arsenite treated SV-HUC-1 cells. Taken together, these results provide new insights into mTORC1/HIF-1α and PKM2 networks as critical molecular targets that contribute to the arsenic-induced malignant progression of bladder epithelial cells.
砷（As）被认为是一种潜在的环境污染物，与膀胱癌的发生有关。然而，其分子机制尚不清楚。代谢重编程是癌症的标志之一，也是恶性肿瘤的一个核心特征。在这里，我们研究了哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）/缺氧诱导因子 1 ɑ（HIF-1ɑ）通路与有氧糖酵解之间的串扰，以促进体内和体外砷处理的膀胱上皮细胞的增殖和迁移。我们证明亚砷酸盐促进了 N-甲基-N-亚硝脲（MNU）在大鼠膀胱中的肿瘤形成以及人输尿管上皮（SV-HUC-1）细胞的恶性行为。我们发现亚砷酸盐通过葡萄糖转运蛋白 1（GLUT1）正向调节 mTORC1/HIF-1ɑ通路，这涉及到依赖糖酵解的膀胱上皮细胞的恶性进展。此外，亚砷酸盐增加的丙酮酸激酶 M2（PKM2）降低了琥珀酸脱氢酶（SDH）和延胡索酸水合酶（FH）的蛋白表达，导致琥珀酸和延胡索酸的肿瘤代谢物积累。此外，热休克蛋白（HSP）90作为一种伴侣蛋白，稳定 PKM2，从而调节 SV-HUC-1 细胞中砷处理的增殖和有氧糖酵解。总之，这些结果为 mTORC1/HIF-1ɑ和 PKM2 网络作为关键分子靶点提供了新的见解，这些靶点有助于砷诱导的膀胱上皮细胞恶性进展。
