The PPAR gamma ligands PGJ(2) and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines

Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in the control of cell proliferation, apoptosis and differentiation in various tumor cells. Among PPARgamma ligands, 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2)), the ultimate metabolite of PGD(2), plays a role in the biology of brain tumors. It is still unclear to which extent the antiproliferative and differentiation-promoting activity of PGJ(2) is mediated through PPARgamma. We compared the effects of PGJ(2) with those of rosiglitazone - the synthetic agonist with the highest affinity for PPARgamma - in 4 human glioblastoma cell lines (A172, U87-MG, M059K, M059J). All cell lines expressed high levels of PPARgamma, consistent with the high levels of PPARgamma protein in 5 tumor samples. Both PGJ(2) and rosiglitazone inhibited proliferation of all cell lines with a G(2)(/)M arrest and apoptosis, but only PGJ(2) up-regulated p21(Cip/WAF1). The growth inhibitory effect was partially reversed by the PPARgamma antagonist GW9662. We studied the time sequence of selected molecular events, that lead glioblastoma cells to apoptosis and/or differentiation, after treatment with both agonists. M059K cells committed to undergo apoptosis by PGJ(2), initially up-regulated PPARgamma, and then down-regulated PPARgamma as they began apoptosis. Apoptotic cells also increased their expression of retinoic acid receptor beta (RARbeta) and retinoid X receptor alpha (RXRalpha). PGJ(2) increased expression of glial fibrillary acidic protein (GFAP) and decreased levels of vimentin, structural proteins modulated during astrocytic differentiation. Unexpectedly, PGJ(2) up-regulated the expression of cyclooxygenase-2 (COX-2). Rosiglitazone caused the same pattern of PPARgamma, RARbeta and RXRalpha expression as PGJ(2), but no significant modulation of p21(Cip/WAF1), cytoskeletal proteins or COX-2 occurred. Our data indicate that PGJ(2), and rosiglitazone suppress cell proliferation and cause apoptosis in glioblastoma cell lines, most likely through a PPARgamma-dependent pathway. By contrast, the modulation of differentiation-associated proteins by PGJ(2), but not rosiglitazone, suggests that PGJ(2) promotes differentiation of glioblastoma cells independently of PPARgamma activation