Luo Zhuang, Chen Wei, Wu Wenjuan, Luo Wei, Zhu Tingting, Guo Gang, Zhang Liyan, Wang Chu, Li Min, Shi Shaoqing
Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, P.R. China.
Department of Pathophysiology in School of Basic Medical Science, North Sichuan Medical College, Nanchong, P.R. China.
J Cell Biochem. 2019 Jul;120(7):11890-11899. doi: 10.1002/jcb.28470. Epub 2019 Feb 21.
Metformin, a first-line antidiabetic drug, has been reported with anticancer activities in many types of cancer. However, its molecular mechanisms remain largely unknown. As a member of inhibitor of apoptosis proteins, survivin plays an important role in the regulation of cell death. In the present study, we investigated the role of survivin in metformin-induced anticancer activity in non-small cell lung cancer in vitro. Metformin mainly induced apoptotic cell death in A549 and H460 cell lines. It remarkably suppressed the expression of survivin, decreased the stability of this protein, then promoted its proteasomal degradation. Moreover, metformin greatly suppressed protein kinase A (PKA) activity and induced its downstream glycogen synthase kinase 3β (GSK-3β) activation. PKA activators, both 8-Br-cAMP and forskolin, significantly increased the expression of survivin. Consistently both GSK-3β inhibitor LiCl and siRNA restored the expression of survivin in lung cancer cells. Furthermore, metformin induced adenosine 5'-monophosphate-activated protein kinase (AMPK) activation. Suppression of the activity of AMPK with Compound C reversed the degradation of survivin induced by metformin, and meanwhile, restored the activity of PKA and GSK-3β. These results suggest that metformin kills lung cancer cells through AMPK/PKA/GSK-3β-axis-mediated survivin degradation, providing novel insights into the anticancer effects of metformin.
二甲双胍是一种一线抗糖尿病药物，已有报道称其在多种癌症中具有抗癌活性。然而，其分子机制在很大程度上仍不清楚。作为凋亡抑制蛋白家族的一员，生存素在细胞死亡调控中发挥着重要作用。在本研究中，我们在体外研究了生存素在二甲双胍诱导的非小细胞肺癌抗癌活性中的作用。二甲双胍主要诱导A549和H460细胞系发生凋亡性细胞死亡。它显著抑制生存素的表达，降低该蛋白的稳定性，进而促进其蛋白酶体降解。此外，二甲双胍极大地抑制蛋白激酶A（PKA）的活性并诱导其下游糖原合酶激酶3β（GSK-3β）的激活。PKA激活剂8-溴环磷酸腺苷（8-Br-cAMP）和福斯高林均显著增加生存素的表达。同样，GSK-3β抑制剂氯化锂和小干扰RNA（siRNA）均可恢复肺癌细胞中生存素的表达。此外，二甲双胍诱导5'-单磷酸腺苷激活的蛋白激酶（AMPK）的激活。用化合物C抑制AMPK的活性可逆转二甲双胍诱导的生存素降解，同时恢复PKA和GSK-3β的活性。这些结果表明，二甲双胍通过AMPK/PKA/GSK-3β轴介导的生存素降解来杀死肺癌细胞，为二甲双胍的抗癌作用提供了新的见解。
