title: AMPK Causes Cell Cycle Arrest in LKB1-Deficient Cells via Activation of CAMKK2.
abstract: 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 Ca(2+)/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 Ca(2+) ionophore A23187 caused a G1 arrest that correlated with AMPK activation and Thr172 phosphorylation. In G361 cells, expression of a truncated, Ca(2+)/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 reexpressing LKB1 or a constitutively active CAMKK2, or by pharmacologic agents that increase intracellular Ca(2+) and thus activate endogenous CAMKK2.
  
  
  
  Evidence here reveals that the rapid growth and proliferation of cancer cells lacking the tumor suppressor LKB1 is due to reduced activity of AMPK, and suggests a therapeutic approach by which this block might be circumvented. Mol Cancer Res; 14(8); 683-95. ©2016 AACR.
authors.affiliation: Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fogarty
authors.affiliation: Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Ross
authors.affiliation: Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Vara Ciruelos
authors.affiliation: Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gray
authors.affiliation: Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Gowans
authors.affiliation: Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom. d.g.hardie@dundee.ac.uk.
authors.forename: D Grahame
authors.initials: DG
authors.lastname: Hardie
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C517698:CAMKK2 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases