Biomolecules & Therapeutics
Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation
Seung Bae Rho1, Hyun Jung Byun2, Boh-Ram Kim2,* and Chang Hoon Lee2,*
1Division of Translational Science, Research Institute, National Cancer Center, Goyang 10408,
2BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 10326, Republic of Korea
*E-mail: (Kim BR), (Lee CH)
Tel: +82-31-961-5213 (Kim BR), +82-31-961-5213 (Lee CH)
Fax: +82-31-961-5206 (Kim BR), +82-31-961-5206 (Lee CH)
Received: August 7, 2021; Revised: August 31, 2021; Accepted: September 7, 2021; Published online: October 5, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

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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 monophosphateactivated 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: Metformin, LKB1, AMPK, HeLa, Endometrial cancer, Apoptosis

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