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J. Biol. Chem., Vol. 281, Issue 5, 2598-2604, February 3, 2006

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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^*

From the Department of Medicinal Chemistry, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah 84112

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 ,-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 -carbon in these lipids appears to be critical for inhibition because unreactive lipids, e.g. PGB₁, PGE₂, PGF₂, 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.

Received for publication, September 2, 2005 , and in revised form, November 14, 2005.

^* This work was supported in part by United States Public Health Services Grants R01 AI26730 and PO1 CA73992 and the Huntsman Cancer Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a predoctoral fellowship from the American Foundation for Pharmaceutical Education.

² Holds the Dee Glenn and Ida W. Smith Chair for Cancer Research. To whom correspondence should be addressed: Dee Glenn and Ida W. Smith Chair of Cancer Research, Huntsman Cancer Institute, 2000 Circle of Hope, University of Utah, Salt Lake City, UT 84112-5550. Tel.: 801-581-6204; Fax: 801-585-0011; E-mail: frank.fitzpatrick{at}hci.utah.edu.

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