Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad

• Type of Material: Article
• Authors: Raluca Rusovici, Emory University; Amr Ghaleb, Emory University; Hyunsuk Shim, Emory University; Vincent W. Yang, Emory University; Chris Yun, Emory University
• Language: English
• Date: 2007-08
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2007 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016%2Fj.bbagen.2007.04.008
• Title of Journal or Parent Work: BBA - Biochimica et Biophysica Acta
• ISSN: 0006-3002
• Volume: 1770
• Issue: 8
• Start Page: 1194
• End Page: 1203
• Grant/Funding Information: R.R. is supported a Research Fellowship Award from the Crohn’s and Colitis Foundation of America.; H.S. and V.W.Y. are recipients of Georgia Cancer Coalition Distinguished Cancer Scientist Awards.; This work was supported by NIH grants (DK071597 and DK64399) and by the Emory University Research Committee.
• Keywords: MAPK; lysophosphatidic acids; apoptosis; receptor
• Research Categories: Health Sciences, Oncology; Biology, Physiology

Abstract

Lysophosphatidic acids (LPA) exert growth factor-like effects through specific G protein-coupled receptors. The presence of different LPA receptors often determines the specific signaling mechanisms and the physiological consequences of LPA in different environments. Among the four members of the LPA receptor family, LPA2 has been shown to be overexpressed in colon cancer suggesting that the signaling by LPA2 may potentiate growth and survival of tumor cells. In this study, we examined the effect of LPA on survival of colon cancer cells using Caco-2 cells as a cell model system. LPA rescued Caco-2 cells from apoptosis elicited by the chemotherapeutic drug, etoposide. This protection was accompanied by abrogation of etoposide-induced stimulation of caspase activity via a mechanism dependent on Erk and PI3K. In contrast, perturbation of cellular signaling mediated by the LPA2 receptor by knockdown of a scaffold protein NHERF2 abrogated the protective effect of LPA. Etoposide decreased the expression of Bcl-2, which was reversed by LPA. Etoposide decreased the phosphorylation level of the proapoptotic protein Bad in an Erk-dependent manner, without changing Bad expression. We further show that LPA treatment resulted in delayed activation of Erk. These results indicate that LPA protects Caco-2 cells from apoptotic insult by a mechanism involving Erk, Bad, and Bcl-2.