Transforming growth factor-β (TGF-β) activates cytosolic phospholipase A2α (cPLA2α)-mediated prostaglandin E2 (PGE2) /EP1 and peroxisome proliferator-activated receptor-γ (see abstract)

Abstract

Transforming growth factor-β (TGF-β) potently inhibits the growth of human epithelial cells. However, neoplastic epithelial cells become resistant to TGF-β-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 A2α (cPLA2α)-controlled eicosanoid metabolism and the growth response to TGF-β in human liver cancer cells. TGF-β treatment induced simultaneous Smad-mediated gene transcription and phosphorylation of cPLA2α. Whereas Smad activation inhibited tumor cell growth, phosphorylation of CPLA 2α promoted growth and counteracted Smad-mediated mitoinhibition. TGF-β1 failed to prevent the growth off cells with high basal expression of cPLA2α, but inhibition of CPLA 2α, cyclooxygenase-2 (COX-2), or EP1 receptor restored mitoinhibition by TGF-β1 in these cells. These results suggest that resistance of tumor cells to TGF-β-mediated mitoinhibition involves activation of cPLA2α/COX-2/EP1 signaling. Furthermore, the TGF-β1-induced Smad transcriptional activity and mitoinhibition were blocked by overespression of cPLA2α or peroxisome proliferator-activated receptor-γ (PPAR-γ) but enhanced by depletion of cPLA2α or PPAR-γ. These findings, along with the observations that cPLA2α activates PPAR-γ and that PPAR-γ binds Smad3, illustrate novel cPLA2α/COX-2/ EP1 and cPLA2α/PPAR-γ/Smad signaling pathways that counteract the mitoinhibition by TGF-β in human cancer cells.