Abstract
Transforming growth factor-beta (TGF-beta) potently inhibits the growth of human epithelial cells. However, neoplastic epithelial cells become resistant to TGF-beta-mediated mitoinhibition, and the mechanisms for this alteration during tumorigenesis are not fully understood. This study was designed to determine whether there is an association between the cytosolic phospholipase A2alpha (cPLA2alpha)-controlled eicosanoid metabolism and the growth response to TGF-beta in human liver cancer cells. TGF-beta treatment induced simultaneous Smad-mediated gene transcription and phosphorylation of cPLA2alpha. Whereas Smad activation inhibited tumor cell growth, phosphorylation of cPLA2 alpha promoted growth and counteracted Smad-mediated mitoinhibition. TGF-beta1 failed to prevent the growth of cells with high basal expression of cPLA2alpha, but inhibition of cPLA2 alpha, cyclooxygenase-2 (COX-2), or EP1 receptor restored mitoinhibition by TGF-beta1 in these cells. These results suggest that resistance of tumor cells to TGF-beta-mediated mitoinhibition involves activation of cPLA2alpha/COX-2/EP1 signaling. Furthermore, the TGF-beta1-induced Smad transcriptional activity and mitoinhibition were blocked by overexpression of cPLA2alpha or peroxisome proliferator-activated receptor-gamma (PPAR-gamma) but enhanced by depletion of cPLA2alpha or PPAR-gamma. These findings, along with the observations that cPLA2alpha activates PPAR-gamma and that PPAR-gamma binds Smad3, illustrate novel cPLA2alpha/COX-2/EP1 and cPLA2alpha/PPAR-gamma/Smad signaling pathways that counteract the mitoinhibition by TGF-beta in human cancer cells.
Highlights
Transforming Growth Factor- (TGF-) Activates Cytosolic Phospholipase A2␣-mediated Prostaglandin E2 (PGE2)/EP1 and Peroxisome Proliferator-activated Receptor-␥ (PPAR-␥)/Smad Signaling Pathways in Human Liver Cancer Cells
The current rationalization for the paradoxical effects of TGF-s on tumor growth is that TGF-s function as tumor suppressors early in tumorigenesis when epithelial cell responnal-regulated kinase; PBS, phosphate-buffered saline; PBS-T, 0.5% Tween 20 in PBS; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; siRNA, small interfering RNA; PPRE, peroxisome proliferator-response element
D, TGF-1 had no effect on cPLA2␣ and COX-2 protein levels in human liver cancer cells
Summary
44344 –44354, 2004 Printed in U.S.A. Transforming Growth Factor- (TGF-) Activates Cytosolic Phospholipase A2␣ (cPLA2␣)-mediated Prostaglandin E2 (PGE2)/EP1 and Peroxisome Proliferator-activated Receptor-␥ (PPAR-␥)/Smad Signaling Pathways in Human Liver Cancer Cells. The TGF-1-induced Smad transcriptional activity and mitoinhibition were blocked by overexpression of cPLA2␣ or peroxisome proliferatoractivated receptor-␥ (PPAR-␥) but enhanced by depletion of cPLA2␣ or PPAR-␥ These findings, along with the observations that cPLA2␣ activates PPAR-␥ and that PPAR-␥ binds Smad, illustrate novel cPLA2␣/COX-2/ EP1 and cPLA2␣/PPAR-␥/Smad signaling pathways that counteract the mitoinhibition by TGF- in human cancer cells. Whereas Smad activation inhibits tumor cell growth, phosphorylation of cPLA2␣ initiates two signaling pathways that counteract Smad-mediated mitoinhibition, including production of PGE2 for activation of its G-protein-coupled plasma membrane receptor EP1 and activation of nuclear eicosanoid receptor PPAR-␥. Our findings establish a novel link between two individual signaling cascades that are important for control of tumor growth
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