Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation

  • Rho, Seung Bae (Division of Translational Science, Research Institute, National Cancer Center) ;
  • Byun, Hyun Jung (BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University) ;
  • Kim, Boh-Ram (BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University) ;
  • Lee, Chang Hoon (BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University)
  • Received : 2021.08.07
  • Accepted : 2021.09.07
  • Published : 2021.11.01
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Abstract

Metformin is an anti-diabetic drug and has anticancer effects on various cancers. Several studies have suggested that metformin reduces cell proliferation and stimulates cell-cycle arrest and apoptosis. However, the definitive molecular mechanism of metformin in the pathophysiological signaling in endometrial tumorigenesis and metastasis is not clearly understood. In this study, we examined the effects of metformin on the cell viability and apoptosis of human cervical HeLa and endometrial HEC-1-A and KLE cancer cells. Metformin suppressed cell growth in a dose-dependent manner and dramatically evoked apoptosis in HeLa cervical cancer cells, while apoptotic cell death and growth inhibition were not observed in endometrial (HEC-1-A, KLE) cell lines. Accordingly, the p27 and p21 promoter activities were enhanced while Bcl-2 and IL-6 activities were significantly reduced by metformin treatment. Metformin diminished the phosphorylation of mTOR, p70S6K and 4E-BP1 by accelerating adenosine monophosphate-activated kinase (AMPK) in HeLa cancer cells, but it did not affect other cell lines. To determine why the anti-proliferative effects are observed only in HeLa cells, we examined the expression level of liver kinase B1 (LKB1) since metformin and LKB1 share the same signalling system, and we found that the LKB1 gene is not expressed only in HeLa cancer cells. Consistently, the overexpression of LKB1 in HeLa cancer cells prevented metformin-triggered apoptosis while LKB1 knockdown significantly increased apoptosis in HEC-1-A and KLE cancer cells. Taken together, these findings indicate an underlying biological/physiological molecular function specifically for metformin-triggered apoptosis dependent on the presence of the LKB1 gene in tumorigenesis.

Keywords

Acknowledgement

This study was partially supported by a grant from the National Cancer Center (NCC-0810410-3), BK21 FOUR program, the Basic Science Research Program, through the National Research Foundation (NRF) of Korea (NRF-2020R1A2C3004973, NRF-2018R1A5A2023127, NRF-2020M3E5E2038356), and Global PhD. Fellowship through the NRF of Korea (NRF-2018H1A2A1061990). We would like to thank Dr. Richard Yoo (University of Michigan at Ann Arbor, USA) for critically reading of the manuscript.

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