Liver Kinase B1/Adenosine Monophosphate-Activated Protein Kinase Signaling Axis Induces P21/Waf1 Expression In A P53-Dependent Manner

Liver kinase B1 (LKB1) encodes a serine/threonine kinase and functions as a tumor suppressor. LKB1 loss-of-function somatic mutations are frequently observed in sporadic types of cancer, particularly in lung cancer. Ectopic LKB1 induces growth arrest by upregulating p21/cyclin dependent kinase inhibitor IA (WAFI) in LKB1 deficient cervical and melanoma cancer cell lines. However, the underlying molecular mechanism remains to be elucidated. The present study built upon previous observations by confirming that the ectopic expression level of LKB1 significantly reduced colony formation of LKB1-deficient lung cancer cells. Mechanistically, the present study demonstrated that LKB1 overexpression significantly induced p21/WAF1 expression in a kinase-dependent manner. Conversely, LKB1 stable knockdown resulted in a decrease in p21 WAF1 expression level in colon cancer cells. In addition, it was revealed that pharmacological activation of adenosine monophosphate protein kinase (AMPK) by 2-deoxyglucose significantly increased the p21/WAF1 expression level, suggesting that AMPK acts downstream of LKB1 to induce p21/WAFI expression. Furthermore, the present study demonstrated that functional p53 was required for p21/WAF1 induction by LKB1. Phosphorylation of p53-Ser(15) was increased by ectopic LKB1 or AMPK activation. Taken together, these results suggested that LKB1 acts via its substrate, AMPK, to upregulate p21/WAF1 expression in a p53-dependent manner. Therefore, the present study identified an important signaling axis, providing novel molecular insights into the tumor suppressor role of LKB1.