Lysophosphatidic Acid Regulation and Roles in Human Prostate Cancer
Final rept. 2 Jan 2002-31 Jul 2006
VIRGINIA COMMONWEALTH UNIV RICHMOND
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The bioactive phospholipids, lysophosphatidic acid LPA and phosphatidic acid PA, regulate pivotal processes related to the pathogenesis of cancer. We characterized a novel lipid kinase, designated acylglycerol kinase AGK, that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively. Confocal microscopy and subcellular fractionation suggest that AGK is localized to the mitochondria. AGK expression was up-regulated in prostate cancers compared with normal prostate tissues from the same patient. Expression of AGK in PC-3 prostate cancer cells markedly increased formation and secretion of LPA. This increase resulted in concomitant transactivation of the EGF receptor and sustained activation of extracellular signal related kinase ERK 12, culminating in enhanced cell proliferation. AGK expression also increased migratory responses. Conversely, down-regulating expression of endogenous AGK inhibited EGF- but not LPA-induced ERK12 activation and progression through the S phase of the cell cycle. Hence, AGK can amplify EGF signaling pathways and may play an important role in the pathophysiology of prostate cancer. Therefore, targeting this kinase, offers additional therapeutic benefits in treatment of androgen-independent prostate cancer.
- Medicine and Medical Research