RETRACTED: Transforming growth factor-β (TGF-β) activates cytosolic phospholipase A2α (cPLA2α)-mediated prostaglandin E2 (PGE2)/EP1 and peroxisome proliferator-activated receptor-γ (PPAR-γ)/Smad signaling pathways in human liver cancer cells - A novel mechanism for subversion of TGF-β-induced mitoinhibition (Retracted Article)

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 A(2)alpha (cPLA(2)alpha)-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 cPLA(2)alpha. Whereas Smad activation inhibited tumor cell growth, phosphorylation of cPLA(2)alpha promoted growth and counteracted Smad-mediated mitoinhibition. TGF-beta1 failed to prevent the growth of cells with high basal expression of cPLA(2)alpha, but inhibition of cPLA(2)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 cPLA(2)alpha/COX-2/EP1 signaling. Furthermore, the TGF-beta1-induced Smad transcriptional activity and mitoinhibition were blocked by overexpression of cPLA(2)alpha or peroxisome proliferator-activated receptor-gamma (PPAR-gamma) but enhanced by depletion of cPLA(2)alpha or PPAR-gamma. These findings, along with the observations that cPLA(2)alpha activates PPAR-gamma and that PPAR-gamma binds Smad3, illustrate novel cPLA(2)alpha/COX-2/EP1 and cPLA(2)alpha/PPAR-gamma/Smad signaling pathways that counteract the mitoinhibition by TGF-beta in human cancer cells.