Department of Oncology, The Affiliated Wujin People's Hospital, Jiangsu University, Changzhou, Jiangsu Province. 213162, People's Republic of China; Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, 212000, People's Republic of China.
Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, 212000, People's Republic of China.
Eur J Pharmacol. 2019 Nov 15;863:172664. doi: 10.1016/j.ejphar.2019.172664. Epub 2019 Sep 17.
As a nuclear receptor, peroxisome-proliferator-activated receptor α (PPARα) plays a critical role in regulation of metabolism and cancer, while the effect of PPARα agonist on cancer cell glucose metabolism-linked tumor growth is still unclear. Here we found that PPARα agonist (Wy14,643) decreased Glut1 (Glucose transporter 1) gene and protein expressions of colorectal cancer cell lines in response to normoxia or hypoxia. Dual-luciferase analysis showed that Wy14,643 inhibited Glut1 transcription activity. Importantly, ChIP-qPCR analysis showed that Wy14,643 increased the binding of PPARα to Glut1 promoter region. Wy14,643 suppressed Glut1 transcription activity resulting in reduced influx of glucose in cancer cells in response to normoxia or hypoxia. Further analysis showed that Wy14,643-mediated inhibition of tumor growth and chemo-resistance was associated with inhibition of mTOR pathway. Taken together, PPARα agonist Wy14,643 suppressed Glut1 transcription activity, glucose uptake and mTOR pathway in colorectal cancer cells, which was involved in reduced tumor growth and chemo-resistance. These findings provided a novel therapy strategy for cancer progression.
作为核受体，过氧化物酶体增殖物激活受体α（PPARα）在调节代谢和癌症方面发挥着关键作用，而 PPARα 激动剂对癌细胞葡萄糖代谢相关肿瘤生长的影响尚不清楚。在这里，我们发现 PPARα 激动剂（WY14,643）在常氧或低氧条件下降低了结肠直肠癌细胞系中 Glut1（葡萄糖转运蛋白 1）基因和蛋白的表达。双荧光素酶分析表明，WY14,643 抑制 Glut1 转录活性。重要的是，ChIP-qPCR 分析表明，WY14,643 增加了 PPARα 与 Glut1 启动子区域的结合。WY14,643 抑制 Glut1 转录活性，导致常氧或低氧条件下癌细胞中葡萄糖的摄取减少。进一步的分析表明，WY14,643 介导的肿瘤生长和化疗耐药性的抑制与 mTOR 通路的抑制有关。总之，PPARα 激动剂 WY14,643 抑制了结肠直肠癌细胞中的 Glut1 转录活性、葡萄糖摄取和 mTOR 通路，这与肿瘤生长和化疗耐药性的降低有关。这些发现为癌症进展提供了一种新的治疗策略。
