Metformin impairs the growth of liver kinase B1-intact cervical cancer cells.
OBJECTIVE
Metformin is one of the most widely used drugs for the treatment of type 2 diabetes. Recent investigations demonstrated that application of metformin reduces cancer risk. The present study aimed to determine the role of liver kinase B1 (LKB1) in the response of cervical cancer cells to metformin.


METHODS
LKB1 expression and the integrity of LKB1-AMPK signaling were determined with immunoblot in 6 cervical cancer cell lines. Cellular sensitivity to metformin was analyzed with MTT assay.


RESULTS
Metformin inhibited growth of cervical cancer cells, C33A, Me180, and CaSki, but was less effective against HeLa, HT-3, and MS751 cells. Analyzing the expression status and the integrity of LKB1-AMPK-mTOR signaling, we found that cervical cancer cells sensitive to metformin were LKB1 intact and exerted an integral AMPK-mTOR signaling response after the treatment. Ectopic expression of LKB1 with stable transduction system or inducible expression construct in endogenous LKB1 deficient cells improved the activation of AMPK, promoted the inhibition of mTOR, and prompted the sensitivity of cells to metformin. In contrast, knock-down of LKB1 compromised cellular response to metformin. Our further investigation demonstrated that metformin could induce both apoptosis and autophagy in cervical cancer cells when LKB1 is expressed.


CONCLUSIONS
Metformin is a potential drug for the treatment of cervical cancers, in particular to those with intact LKB1 expression. Administration of cell metabolism agonists may enhance LKB1 tumor suppression, inhibit cell growth, and reduce tumor cell viability via the activation of LKB1-AMPK signaling.
Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Xuxian
X
Xiao
Qiongqiong
Q
He
Changming
C
Lu
Kaitlin D
KD
Werle
Rui-Xun
RX
Zhao
Jianfeng
J
Chen
Ben C
BC
Davis
Rutao
R
Cui
Jiyong
J
Liang
Zhi-Xiang
ZX
Xu
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology
D008687:Metformin; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases