Metformin induces apoptosis of lung cancer cells through activating JNK/p38 MAPK pathway and GADD153

Neoplasma. 2011;58(6):482-90. doi: 10.4149/neo_2011_06_482.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / pathology
  • Animals
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Proliferation
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Immunoenzyme Techniques
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology*
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism*
  • Metformin / therapeutic use*
  • Mice
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor CHOP / antagonists & inhibitors
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Hypoglycemic Agents
  • RNA, Messenger
  • RNA, Small Interfering
  • Transcription Factor CHOP
  • Metformin
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4