Reactive lipid species from cyclooxygenase-2 inactivate tumor suppressor LKB1/STK11: cyclopentenone prostaglandins and 4-hydroxy-2-nonenal covalently modify and inhibit the AMP-kinase kinase that modulates cellular energy homeostasis and protein translation.
LKB1, a unique serine/threonine kinase tumor suppressor, modulates anabolic and catabolic homeostasis, cell proliferation, and organ polarity. Chemically reactive lipids, e.g. cyclopentenone prostaglandins, formed a covalent adduct with LKB1 in MCF-7 and RKO cells. Site-directed mutagenesis implicated Cys210 in the LKB1 activation loop as the residue modified. Notably, ERK, JNK, and AKT serine/threonine kinases with leucine or methionine, instead of cysteine, in their activation loop did not form a covalent lipid adduct. 4-Hydroxy-2-nonenal, 4-oxo-2-nonenal, and cyclopentenone prostaglandin A and J, which all contain alpha,beta-unsaturated carbonyls, inhibited the AMP-kinase kinase activity of cellular LKB1. In turn, this attenuated signals throughout the LKB1 --> AMP kinase pathway and disrupted its restraint of ribosomal S6 kinases. The electrophilic beta-carbon in these lipids appears to be critical for inhibition because unreactive lipids, e.g. PGB1, PGE2, PGF2alpha, and TxB2, did not inhibit LKB1 activity (p > 0.05). Ectopic expression of cyclooxygenase-2 and endogenous biosynthesis of eicosanoids also inhibited LKB1 activity in MCF-7 cells. Our results suggested a molecular mechanism whereby chronic inflammation or oxidative stress may confer risk for hypertrophic or neoplastic diseases. Moreover, chemical inactivation of LKB1 may interfere with its physiological antagonism of signals from growth factors, insulin, and oncogenes.
Wagner
Tracy M
TM
Department of Medicinal Chemistry, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah 84112, USA.
Mullally
James E
JE
Fitzpatrick
F A
FA
D000091162:AMP-Activated Protein Kinase Kinases; D000447:Aldehydes; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D003517:Cyclopentanes; D004734:Energy Metabolism; D006801:Humans; D008055:Lipids; D016297:Mutagenesis, Site-Directed; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism*; D011453:Prostaglandins / Q000737:chemistry*; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*
D000447:Aldehydes; D003517:Cyclopentanes; D008055:Lipids; D011453:Prostaglandins; D051546:Cyclooxygenase 2; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; C118888:AMP-dependent kinase (ATP-forming); D017856:Phosphotransferases (Phosphate Group Acceptor); C027576:4-hydroxy-2-nonenal; C013905:cyclopentenone