Department of Respiratory Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China.
Neoplasma. 2011;58(6):482-90. doi: 10.4149/neo_2011_06_482.
There are epidemiological and experimental evidences that metformin, an insulin-sensitizer agent widely used for diabetes treatment, has inhibitory effects on the growth of various human cancers. However, the underlying molecular mechanisms for its anti-neoplastic activity has not been yet clarified and the effect of metformin on human lung cancer remains unknown. In this study we revealed for the first time that metformin treatment led to increased apoptosis in human lung cancer cell lines A549 and NCI-H1299 and significantly inhibited the cells proliferation in a dose- and time-dependent manner, which was further demonstrated by the data obtained from A549 tumor xenografts in nude mice. We also found that metformin treatment can activate AMP-activated protein kinase, JNK/p38 MAPK signaling pathway and caspases, as well as upregulate the expression of growth arrest and DNA damage inducible gene 153 (GADD153). Either blockade of JNK/p38 MAPK pathway or knockdown of GADD153 gene abrogated the apoptosis-inducing effect of metformin. Taken together, our data suggest that metformin inhibits the growth of lung cancer cells and induces apoptosis through activating JNK/p38 MAPK pathway and GADD153.
有流行病学和实验证据表明，二甲双胍作为一种广泛用于糖尿病治疗的胰岛素增敏剂，对多种人类癌症的生长具有抑制作用。然而，其抗肿瘤活性的潜在分子机制尚不清楚，二甲双胍对人类肺癌的影响也尚不清楚。在这项研究中，我们首次揭示了二甲双胍治疗可导致人肺癌细胞系 A549 和 NCI-H1299 凋亡增加，并呈剂量和时间依赖性显著抑制细胞增殖，这进一步从裸鼠 A549 肿瘤异种移植中获得的数据得到证实。我们还发现，二甲双胍治疗可激活 AMP 激活的蛋白激酶、JNK/p38 MAPK 信号通路和半胱天冬酶，同时上调生长停滞和 DNA 损伤诱导基因 153（GADD153）的表达。阻断 JNK/p38 MAPK 通路或敲低 GADD153 基因均可消除二甲双胍的促凋亡作用。总之，我们的数据表明，二甲双胍通过激活 JNK/p38 MAPK 通路和 GADD153 抑制肺癌细胞生长并诱导细胞凋亡。
