Lysophosphatidic Acid Decreases the Nuclear Localization and Cellular Abundance of the p53 Tumor Suppressor in A549 Lung Carcinoma Cells

Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid that promotes cancer cell proliferation and motility through activation of cell surface G protein -coupled receptors. Here, we provide the first evidence that LPA reduces the cellular abundance of the tumor suppressor p53 in A549 lung carcinoma cells, which express endogenous LPA receptors. The LPA effect depends on increased proteasomal degradation of p53 and it results in a corresponding decrease in p53-mediated transcription. Inhibition of phosphatidylinositol 3-kinase protected cells from the LPA-induced reduction of p53, which implicates this signaling pathway in the mechanism of LPA-induced loss of p53. LPA partially protected A549 cells from actinomycin D induction of both apoptosis and increased p53 abundance. Expression of LPA 1 , LPA 2 , and LPA 3 receptors in HepG2 hepatoma cells, which normally do not respond to LPA, also decreased p53 expression and p53-dependent transcription. In contrast, neither inactive LPA 1 (R124A) nor another G i -coupled receptor, the M 2 muscarinic acetylcholine receptor, reduced p53-dependent transcription in HepG2 cells. These results identify p53 as a target of LPA action and provide a new dimension for understanding how LPA stimulates cancer cell division, protects against apoptosis, and thereby promotes tumor progression.

Regulation of Hypoxia-inducible Factor 1α (HIF-1α) by Lysophosphatidic Acid Is Dependent on Interplay between p53 and Krüppel-like Factor 5

“…Our finding that LPA down-regulated p53 in colon cancer cells is consistent with a previous report that LPA decreased nuclear and cellular p53 expression in A549 lung carcinoma and HepG2 hepatocellular carcinoma cells (29). Consistently, LPA induces HIF-1␣ and VEGF expression in SK-Hep1 cells with wtp53 but not in p53-null Hep-3b cells (41,42).…”

“…Unlike HCT116 and LoVo cells, which express wild type p53 (wtp53), HT-29 and SW480 cells harbor mutant p53 (mutp53) (28). It was shown previously that LPA decreases p53-dependent transcription (29), and hence we determined p53 expression in cells treated with LPA. Although p53 levels at the resting state were low, LPA clearly decreased p53 protein levels in HCT116 and LoVo cells.…”

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

“…These signaling cascades include phosphatidylinositol 3-kinase (PI3K) and Akt, the extracellular signal-regulated kinase (ERK) pathway, and the small G-protein, RhoA, that mediates cell survival (Ye et al, 2002;Tigyi and Parrill, 2003;RadeffHuang et al, 2004). Activation of LPA receptors also decreases the abundance of the p53 tumor suppressor, thereby promoting cell survival and cell cycle progression (Murph et al, 2007).…”

Suppression of the p53-Dependent Replicative Senescence Response by Lysophosphatidic Acid Signaling

“…It was recently reported that LPA signaling can lead to downregulation of p53 function by reduction of the nuclear fraction of the protein (54). We therefore investigated the function and localization of p53 in the immortalized LPA 2 MEFs.…”

“…Our findings are consistent with a model in which enhanced LPA signaling can bypass potent tumor-suppressive p53-dependent signaling to mediate escape from replicative senescence. Murph et al (54) recently reported that LPA signaling reduced p53 transcriptional activity and nuclear p53 protein abundance in A549 lung carcinoma cells. In contrast, we find that LPA 2 -immortalized cells retain a functional p53 response following treatment with a DNA-damaging agent (Fig.…”