Exogenous activation of LKB1/AMPK signaling induces G₁ arrest in cells with endogenous LKB1 expression.
The tumor suppressor protein LKB1 is a serine/threonine kinase that plays a critical role in cell proliferation, and its inactivation has been linked to tumorigenesis in various cancer types. Current understanding of the LKB1 function is largely restricted to results from experiments on LKB1‑deficient cancer cells, while the regulation and activity of endogenous LKB1 has been rarely investigated. In a previous study, we showed that LKB1 knockdown in two healthy cell lines accelerates cell cycle progression through the G1/S checkpoint by inhibition of the p53 and p16 pathways. In the present study, we examined the effects of overexpression of LKB1 on two healthy and one cancer cell line. Administration of exogenous LKB1 activated LKB1/AMPK signaling and arrested the cell cycle at the G1 phase in an LKB1-dependent manner. G1 arrest induced by LKB1 was accompanied by the downregulation of cyclin D1 and cyclin D3, and the upregulation of p53, p21 and p16, while no differences were detected for CDK4, CDK6, cyclin E, p15 and p27. These results indicated that exogenous activation of LKB1/AMPK signaling inhibits the G1/S cell cycle transition, even in cells with an endogenous expression of LKB1. Findings of the present study extend earlier observations on LKB1‑inactivated neoplastic cells and provide novel insights into the growth-inhibitory effects of LKB1.
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Xiaoyan
X
Liang
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Pilong
P
Wang
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Qing
Q
Gao
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Xiaohong
X
Tao
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D056743:Cyclin D3 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D056743:Cyclin D3; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases