Lysophosphatidic acid decreases the nuclear localization and cellular abundance of the p53 tumor suppressor in A549 lung carcinoma cells.
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.
Murph
Mandi M
MM
School of Biology, Georgia Institute of Technology, Atlanta, Georgia , USA.
Hurst-Kennedy
Jennifer
J
Newton
Victoria
V
Brindley
David N
DN
Radhakrishna
Harish
H
D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D008175:Lung Neoplasms; D008246:Lysophospholipids / Q000633:toxicity*; D008934:Mitogens / Q000633:toxicity*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008246:Lysophospholipids; D008934:Mitogens; D049368:Receptors, Lysophosphatidic Acid; D016159:Tumor Suppressor Protein p53; C032881:lysophosphatidic acid