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J. Biol. Chem., Vol. 282, Issue 21, 15541-15549, May 25, 2007

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Lysophosphatidic Acid Facilitates Proliferation of Colon Cancer Cells via Induction of Krüppel-like Factor 5^*

Huanchun Zhang, Agnieszka Bialkowska, Raluca Rusovici¹, Sengthong Chanchevalap, Hyunsuk Shim², Jonathan P. Katz^¶, Vincent W. Yang², and C. Chris Yun³

From the Division of Digestive Diseases, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322 and the ^¶Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Among the multiple cellular effects mediated by lysophosphatidic acid (LPA), the effect on cell proliferation has extensively been investigated. A recent study showed that LPA-mediated proliferation of colon cancer cells requires activation of -catenin. However, the majority of colon cancer cells have deregulation of the Wnt/-catenin pathway. This prompted us to hypothesize the presence of additional pathway(s) activated by LPA resulting in an increase in the proliferation of colon cancer cells. Krüppel-like factor 5 (KLF5) is a transcriptional factor highly expressed in the crypt compartment of the intestinal epithelium. In this work, we investigated a role of KLF5 in LPA-mediated proliferation. We show that LPA stimulated the expression levels of KLF5 mRNA and protein in colon cancer cells and this stimulation was mediated by LPA₂ and LPA₃. Silencing of KLF5 expression by small interfering RNA significantly attenuated LPA-mediated proliferation of SW480 and HCT116 cells. LPA-mediated KLF5 induction was partially blocked by inhibition of the mitogen-activated protein kinase kinase and protein kinase C-. Moreover, we observed that LPA regulates KLF5 expression via eukaryotic elongation factor 2 kinase (eEF2k). Inhibition of calmodulin or silencing of eEF2k blocked the stimulation in KLF5 expression. Knockdown of eEF2k specifically inhibited KLF5 induction by LPA but not by fetal bovine serum or phorbol 12-myristate 13-acetate. These results identify KLF5 as a target of LPA-mediated signaling and suggest a role of KLF5 in promoting proliferation of intestinal epithelia in response to LPA.

Received for publication, January 24, 2007 , and in revised form, April 9, 2007.

^* This work was supported in part by National Institutes of Health Grant DK071597, the Emory University Research Committee, and a Pilot & Feasibility Grant DK64399 from the Digestive Diseases Research Development Center. 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 research fellowship award from the Crohn and Colitis Foundation of America.

² Recipients of Georgia Cancer Coalition Distinguished Cancer Scientist Awards.

³ To whom correspondence should be addressed: Whitehead Bldg., Rm. 201, 615 Michael St., Atlanta, GA 30322. Tel.: 404-712-2865; Fax: 404-727-5767; E-mail: ccyun{at}emory.edu.

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