Role of Peroxisome Proliferator-Activated Receptor-γ and Its Coactivator DRIP205 in Cellular Responses to CDDO (RTA-401) in Acute Myelogenous Leukemia

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) 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 PPAR gamma protein in a series of 260 newly diagnosed primary acute myelogenous leukemia (AML) samples. Forced expression of PPAR gamma enhanced the sensitivity of myeloid leukemic cells to apoptosis induced by PPAR gamma agonists 2-cyano-3,12-dioxooleana- 1,9-dien-28-oic acid (CDDO) and 15-deoxy-(12,14)-15DPGJ(2), through preferential cleavage of caspase-8. No effects on cell cycle distribution or differentiation were noted, despite prominent induction of p21 in PPAR gamma-transfected cells. In turn, antagonizing PPAR gamma function by small interfering RNA or pharmacologic PPAR gamma inhibitor significantly diminished apoptosis induction by CDDO. Overexpression of coactivator protein DRIP205 resulted in enhanced differentiation induction by CDDO in AML cells through PPAR gamma 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 PPAR gamma 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 PPAR gamma regulate induction of apoptosis via caspase-8 activation, whereas the coactivator DRIP205 is a determinant of induction of differentiation, in response to PPAR gamma agonists in leukemic cells. Cancer Res; 70(12); 4949-60. (C)2010 AACR.