Metformin induces cell cycle arrest at the G1 phase through E2F8 suppression in lung cancer cells
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Dong Hao Jin1, Yujin Kim1, Bo Bin Lee1, Joungho Han2, Hong Kwan Kim3, Young Mog Shim3 and Duk-Hwan Kim1
1Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 440-746, Korea
2Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, Korea
3Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, Korea
Duk-Hwan Kim, email: firstname.lastname@example.org
Keywords: metformin, lung cancer, cell cycle, E2F8, p21
Received: June 29, 2017 Accepted: September 21, 2017 Published: October 06, 2017
A target molecule responsible for cell cycle arrest by metformin was discovered using a gene chip array in lung cancer cells and the effect of metformin on E2F8 was assessed. The siRNA-mediated knockdown of E2F8 significantly suppressed G1-S progression while ectopic expression of E2F8 relieved metformin-induced G1 arrest. The mRNA levels of p21 were found to be inversely related to those of E2F8 in lung cancer cells while siRNA-mediated knockdown of p21 partly rescued siE2F8-induced arrest of the cell cycle. Metformin had no effect on degradation of E2F8 mRNA. Activation and inhibition of AMPK by AICAR and Dorsomorphin, respectively, did not affect E2F8 suppression by metformin. The clinical significance of E2F8 was analyzed in The Cancer Genome Atlas (TCGA) data. One hundred six (13%) of 848 TCGA lung cancers overexpressed E2F8 mRNA. The overexpression of E2F8 was associated with poor overall survival (adjusted hazard ratio = 1.58, 95% confidence interval = 1.13–2.22; P = 0.008). The present study suggests that metformin may induce cell cycle arrest at the G1 phase by suppressing E2F8 expression in lung cancer cells. In addition, E2F8 may be associated with poor overall survival in lung cancer patients irrespective of histology.
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