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. 2012:2012:483656.
doi: 10.1155/2012/483656. Epub 2012 May 21.

Effects of PPARγ Ligands on Leukemia

Yoko Tabe  1 , Marina Konopleva, Michael Andreeff, Akimichi Ohsaka
Affiliations

Effects of PPARγ Ligands on Leukemia

Yoko Tabe et al. PPAR Res. 2012.

Abstract

Peroxisome proliferator-activated receptors (PPARs) and retinoic acid receptors (RARs), members of the nuclear receptor superfamily, are transcription factors that regulate a variety of important cellular functions. PPARs form heterodimers retinoid X receptor (RXR), an obligate heterodimeric partner for other nuclear receptors. Several novel links between retinoid metabolism and PPAR responses have been identified, and activation of PPAR/RXR expression has been shown to increase response to retinoids. PPARγ has emerged as a key regulator of cell growth and survival, whose activity is modulated by a number of synthetic and natural ligands. While clinical trials in cancer patients with thiazolidinediones (TZD) have been disappointing, novel structurally different PPARγ ligands, including triterpenoids, have entered clinical arena as therapeutic agents for epithelial and hematopoietic malignancies. Here we shall review the antitumor advances of PPARγ, alone and in combination with RARα ligands in control of cell proliferation, differentiation, and apoptosis and their potential therapeutic applications in hematological malignancies.

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Figures

Figure 1
Figure 1
Molecular structure of CDDO 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO).
Figure 2
Figure 2
CDDO augments ATRA-induced reactivation of RARβ2 in APL via histone acetylation. Combination of all-trans RA (ATRA) and 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) increases H3-Lys9 acetylation in RARβP2 and RARβ2 transcription. CDDO-bound PPARγ may recruit coactivator proteins, including CBP-p300 and SRC-1 to PPARγ/RXR, which in turn induce histone acetylation and reactivation of ATRA target genes. Ac: acetylated histone H3-Lys9, HDAC: histone deacetylase, mSin3: mammalian homolog of the S. cerevisiae corepressor, Sin 3, NCoR: nuclear receptor corepressor, SRC-1: steroid receptor coactivator-1, CBP/p300: CCAAT/enhancer-binding protein, PCAF: P300/CBP-associated factor.
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