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

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, LPA 2 has been shown to be overexpressed in colon cancer suggesting that the signaling by LPA 2 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 LPA 2 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 Erkdependent 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.

Novel Methods for Imaging PET Biomarkers and Gene Therapy of Cancer

“…In support of this hypothesis, it has been shown that PDZ proteins, including NHERF2, interact with the C-terminal DSTL motif of LP A 2 but not with other LP A receptor subtypes (10,12,13 , .. Our new data and previous reports (10,12,20,27) show that both TRIP6 and NHERF2 are involved in LPA-induced ERK and AKT activation . SKOV-3 ovarian cancer cells show very low levels of phosphatase and tensin homolog but high activity of AKT (28,29).…”

“…When TRIP6 or NHERF2 was knocked down to a great extent, it almost completely eliminated LPA-mediated chemoprotection in SKOV -3 cells. Similarly, it has been reported that knockdown of NHERF2 expression abrogates the chemoprotective effect of LP A in colon cancer cells (27).…”

Serum Lysophosphatidic Acid Level in Chronic Myeloid Leukemia

“…The LPA, via Rho/ROCK/actomyosin and Ras/MEKK1, increases the formation of local conjunctiva and increases the migration of cancer cells (25). Similar effects have also been observed in other cancers, including cancers of the stomach, colon, prostate, pancreas, and liver (4,26).…”

Autotaxin protects MCF-7 breast cancer and MDA-MB-435 melanoma cells against Taxol-induced apoptosis

“…In T lymphoblasts, both LPA 1 and LPA 2 promoted LPA-induced survival (Goetzl et al, 1999a). LPA also prevents apoptosis in colon cancer cells through LPA 2 receptor (Rusovici et al, 2007).…”

“…Consequently, it is significant that 0.5-10 mM LPA increased the number of cells that were recovered after Taxol treatment and that were then reflected in the percentage of apoptotic cells recorded in the DAPI and TMRE staining assays. Accumulating evidence shows that LPA promotes survival of ovarian cancer cells (Frankel and Mills, 1996;Goetzl et al, 1999a), renal proximal tubular cells (Levine et al, 1997), lymphoblastoma T cells (Goetzl et al, 1999b), macrophages (Koh et al, 1998), neonatal Schwann cells (Weiner and Chun, 1999), fibroblast (Fang et al, 2000), mesangial cells (Inoue et al, 2001) and colon cancer cells (Rusovici et al, 2007) by preventing apoptosis. Different cell types express different LPA receptors, which have specific roles, and hence the effects of LPA signaling vary from cell to cell.…”