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CaM kinase control of AKT and LNCaP cell survival.

Abstract
AKT and its substrate BAD have been shown to promote prostate cancer cell survival. Agonists, such as carbachol, and hormones that increase intracellular calcium concentration can activate AKT leading to cancer cell survival. The LNCaP prostate cancer cells express the carbachol-sensitive M(3) -subtype of G protein-coupled receptors that cause increases in intracellular calcium and activate the family of Ca(2+) /calmodulin-dependent protein kinases (CaM Ks). One type of CaM Kinase, CaM Kinase Kinase (CaM KK), phosphorylates several substrates including AKT on threonine 308. AKT phosphorylation and activation enhances cell survival through phosphorylation of BAD protein and the subsequent blockade of caspase activation. Our goals were to examine the mechanism of carbachol activation of AKT and BAD in LNCaP prostate cancer cells and evaluate whether CaM KK may be mediating carbachol's activation of AKT and cell survival. Our results suggest that carbachol treatment of LNCaP cells promoted cell survival through CaM KK and its phosphorylation of AKT. The bacterial toxin anisomycin triggered caspase-3 activation in LNCaP cells that was blocked by carbachol in a CaM KK- and AKT-dependent manner. AKT and BAD phosphorylation were blocked by the selective CaM KK inhibitor, STO-609, as well as siRNA directed against CaM KK. BAD phosphorylation was also blocked by treating cells with the AKT inhibitor, AKT-X, as well as siRNA to AKT. Additionally, epinephrine promoted LNCaP cell survival through activation of AKT that was insensitive to STO-609. Taken together these data suggest a survival role for CaM KK operating through AKT and BAD in LNCaP prostate cancer cells.
AuthorsJohn M Schmitt, Samantha Smith, Brendon Hart, Luke Fletcher
JournalJournal of cellular biochemistry (J Cell Biochem) Vol. 113 Issue 5 Pg. 1514-26 (May 2012) ISSN: 1097-4644 [Electronic] United States
PMID22173970 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Wiley Periodicals, Inc.
Chemical References
  • BAD protein, human
  • Caspase Inhibitors
  • Muscarinic Agonists
  • bcl-Associated Death Protein
  • Carbachol
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • Calcium-Calmodulin-Dependent Protein Kinases
  • CASP3 protein, human
  • Caspase 3
Topics
  • Apoptosis (drug effects)
  • Calcium Signaling
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase (metabolism)
  • Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
  • Carbachol (pharmacology)
  • Caspase 3 (metabolism)
  • Caspase Inhibitors
  • Cell Line, Tumor
  • Cell Survival (physiology)
  • Cyclic AMP-Dependent Protein Kinases (metabolism)
  • Enzyme Activation
  • Humans
  • Male
  • Models, Biological
  • Muscarinic Agonists (pharmacology)
  • Phosphorylation
  • Prostatic Neoplasms (metabolism, pathology)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Signal Transduction (drug effects)
  • bcl-Associated Death Protein (metabolism)

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