The altered function and expression if iPLA2-beta in prostate tumor cells
Schuster, David P
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Growth, development, and function of the prostate gland are regulated through the androgen receptor (AR), and prostate cancer is associated with aberrant regulation of the AR. Three isoforms of a recently discovered calcium independent PLA 2 , iPLA 2 -β, are expressed in prostate epithelial cells, and iPLA2-β expression is regulated by androgen. Variable expression of iPLA 2 -β isoforms purportedly results in its altered activity and function. Data presented herein demonstrate that elevated activity of iPLA 2 is associated with malignant prostate tumor cells, and the hypothesis that altered function and expression of iPLA 2 -β occur during prostate tumor progression was tested. Treatment with the specific iPLA 2 inhibitor BEL resulted in of apoptosis in several prostate tumor cells, but did not affect the survival of non-tumorigenic RWPE-1 prostate epithelial cells, suggesting that iPLA 2 regulates a tumor-specific survival pathway. One function attributed to iPLA 2 -β is the regulation of secretion. Secretion of PSA from LNCaP and LNCaP-LN3 prostate tumor cells was inhibited by BEL; however, PSA secretion from LNCaP-Pro5 cells was not. BEL mediated apoptosis correlated with the inhibition of PSA secretion from cells in the LNCaP series, and PSA reversed the apoptosis induced by BEL in LNCaP cells. These data suggest that inhibition of secretion contributed apoptosis. Expression of iPLA 2 -β was variable between a variety of cell lines representing normal, benign, and malignant prostate epithelial cells, RWPE-1 cells expressed three isoforms of iPLA 2 -β, identified as LH-iPLA 2 , SH-iPLA 2 , and ank-iPLA 2 . Ank-iPLA 2 -1 attenuates the activity of iPLA 2 -β, and its expression was markedly reduced or absent from LNCaP and PC-3 prostate tumor cells respectively. Altered regulation of iPLA 2 -β expression was also demonstrated in androgen refractory derivatives of LNCaP cells as compared to the parental LNCaP cells. Induction of LH-iPLA 2 -β by DHT is greater in the highly malignant LNCaP-LN3 cells than in LNCaP cells. In contrast, LNCaP-Pro5 cells express primarily SH-iPLA 2 . These data indicate that changes in the expression of iPLA 2 -β can accompany the development of androgen refractory prostate tumors. Both the secretion of PSA and resistance to BEL induced apoptosis correlated with the expression of the LH-iPLA 2 isoform, suggesting that this isoform may regulate PSA secretion from prostate tumor cells.