The PPARgamma ligands PGJ2 and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines.

Roberta Morosetti, Tiziana Servidei, Massimiliano Mirabella, Sergio Rutella, Annunziato Mangiola, Giulio Maira, Renato Mastrangelo, H. Phillip Koeffler

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Abstract

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-Delta12,14-prostaglandin J2 (PGJ2), the ultimate metabolite of PGD2, plays a role in the biology of brain tumors. It is still unclear to which extent the anti-proliferative and differentiation-promoting activity of PGJ2 is mediated through PPARgamma. We compared the effects of PGJ2 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 PGJ2 and rosiglitazone inhibited proliferation of all cell lines with a G2/M arrest and apoptosis, but only PGJ2 up-regulated p21Cip/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 PGJ2, 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). PGJ2 increased expression of glial fibrillary acidic protein (GFAP) and decreased levels of vimentin, structural proteins modulated during astrocytic differentiation. Unexpectedly, PGJ2 up-regulated the expression of cyclooxygenase-2 (COX-2). Rosiglitazone caused the same pattern of PPARgamma, RARbeta and RXRalpha expression as PGJ2, but no significant modulation of p21Cip/WAF1, cytoskeletal proteins or COX-2 occurred. Our data indicate that PGJ2, 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 PGJ2, but not rosiglitazone, suggests that PGJ2 promotes differentiation of glioblastoma cells independently of PPARgamma activation.

Original languageEnglish
Pages (from-to)493-502
Number of pages10
JournalInternational Journal of Oncology
Volume25
Issue number2
Publication statusPublished - Aug 2004

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rosiglitazone
PPAR gamma
Glioblastoma
Apoptosis
Ligands
Cell Line
Retinoid X Receptor alpha
Cyclooxygenase 2
9-deoxy-delta-9-prostaglandin D2
Cell Differentiation
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The PPARgamma ligands PGJ2 and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines. / Morosetti, Roberta; Servidei, Tiziana; Mirabella, Massimiliano; Rutella, Sergio; Mangiola, Annunziato; Maira, Giulio; Mastrangelo, Renato; Koeffler, H. Phillip.

In: International Journal of Oncology, Vol. 25, No. 2, 08.2004, p. 493-502.

Research output: Contribution to journalArticle

Morosetti, Roberta ; Servidei, Tiziana ; Mirabella, Massimiliano ; Rutella, Sergio ; Mangiola, Annunziato ; Maira, Giulio ; Mastrangelo, Renato ; Koeffler, H. Phillip. / The PPARgamma ligands PGJ2 and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines. In: International Journal of Oncology. 2004 ; Vol. 25, No. 2. pp. 493-502.
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AU - Rutella, Sergio

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AU - Mastrangelo, Renato

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