AMPK Causes G1 Arrest in LKB1-Null Cells by CAMKK2 Pathway

The AMP-activated protein kinase (AMPK) is activated by phosphorylation at Thr172, either by the tumor suppressor kinase LKB1 or by an alternate pathway involving the Ca2+/calmodulin-dependent kinase, CAMKK2. Increases in AMP:ATP and ADP:ATP ratios, signifying energy deficit, promote allosteric activation and net Thr172 phosphorylation mediated by LKB1, so that the LKB1–AMPK pathway acts as an energy sensor. Many tumor cells carry loss-of-function mutations in the STK11 gene encoding LKB1, but LKB1 reexpression in these cells causes cell-cycle arrest. Therefore, it was investigated as to whether arrest by LKB1 is caused by activation of AMPK or of one of the AMPK-related kinases, which are also dependent on LKB1 but are not activated by CAMKK2. In three LKB1-null tumor cell lines, treatment with the Ca2+ ionophore A23187 caused a G1 arrest that correlated with AMPK activation and Thr172 phosphorylation. In G361 cells, expression of a truncated, Ca2+/calmodulin-independent CAMKK2 mutant also caused G1 arrest similar to that caused by expression of LKB1, while expression of a dominant-negative AMPK mutant, or a double knockout of both AMPK-α subunits, also prevented the cell-cycle arrest caused by A23187. These mechanistic findings confirm that AMPK activation triggers cell-cycle arrest, and also suggest that the rapid proliferation of LKB1-null tumor cells is due to lack of the restraining influence of AMPK. However, cell-cycle arrest can be restored by reexpressin...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Cell Cycle and Senescence Source Type: research