Role of peroxisome proliferator-activated receptor-γ and its coactivator DRIP205 in cellular responses to CDDO (RTA-401) in acute myelogenous leukemia

Twee Tsao, Steven Kornblau, Stephen Safe, Julie C. Watt, Vivian Ruvolo, Wenjing Chen, Yihua Qiu, Kevin R. Coombes, Zhenlin Ju, Maen Abdelrahim, Wendy Schober, Xiaoyang Ling, Dimitris Kardassis, Colin Meyer, Aaron Schimmer, Hagop Kantarjian, Michael Andreeff, Marina Konopleva

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor (NR) family of transcription factors with important regulatory roles in cellular growth, differentiation, and apoptosis. Using proteomic analysis, we showed expression of PPARγ protein in a series of 260 newly diagnosed primary acute myelogenous leukemia (AML) samples. Forced expression of PPARγ enhanced the sensitivity of myeloid leukemic cells to apoptosis induced by PPARγ agonists 2-cyano-3,12-dioxooleana-1,9- dien-28-oic acid (CDDO) and 15-deoxy-12,14-15DPGJ2, through preferential cleavage of caspase-8. No effects on cell cycle distribution or differentiation were noted, despite prominent induction of p21 in PPARγ-transfected cells. In turn, antagonizing PPARγ function by small interfering RNA or pharmacologic PPARγ inhibitor significantly diminished apoptosis induction by CDDO. Overexpression of coactivator protein DRIP205 resulted in enhanced differentiation induction by CDDO in AML cells through PPARγ activation. Studies with DRIP205 deletion constructs showed that the NR boxes of DRIP205 are not required for this coactivation. In a phase I clinical trial of CDDO (RTA-401) in leukemia, CDDO induced an increase in PPARγ mRNA expression in six of nine patient samples; of those, induction of differentiation was documented in four patients and that of p21 in three patients, all expressing DRIP205 protein. In summary, these findings suggest that cellular levels of PPARγ regulate induction of apoptosis via caspase-8 activation, whereas the coactivator DRIP205 is a determinant of induction of differentiation, in response to PPARγ agonists in leukemic cells.

Original languageEnglish (US)
Pages (from-to)4949-4960
Number of pages12
JournalCancer research
Volume70
Issue number12
DOIs
StatePublished - Jun 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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