PPARgamma-active triterpenoid CDDO enhances ATRA-induced differentiation in APL.
Acute promyelocytic leukemia (APL) is associated with oncogenic PML-RARalpha that acts as a dominant negative transcriptional repressor of retinoic acid (RA) receptor target genes by recruiting histone deacetylase (HDAC). The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor family that forms heterodimers with retinoid X receptor (RXR). In addition to RAR targets, PML-RARalpha silence a wide range of nuclear receptor target genes including PPARgamma targets. All-trans-retinoic acid (ATRA), a ligand for the RA receptor (RAR), restores normal retinoid signaling and induces terminal differentiation of APL cells; however, APL cells can develop resistance to ATRA. Using ATRA sensitive NB4 and ATRA-resistant derivative MR2 cell lines, we demonstrate that PPARgamma ligand 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid (CDDO) enhances pro-apoptotic and differentiating effects of ATRA in ATRA-sensitive NB4 cells and partially reverses ATRA resistance in MR2 cells. The CDDO/ATRA combination synergistically induces RARbeta2 expression both in ATRA-sensitive and -resistant APL cells. RARbeta2 MrNA induction by CDDO/ATRA was mediated in part by enhanced H3-Lys9 acetylation in the RARbeta2 promoter which in turn increased the affinity of RARbeta for betaRARE. PPARgamma specific inhibitor T007 and silencing of PPARgamma by siRNA diminished CDDO-induced maturation and RARbeta2 mRNA along with PPARgamma induction indicating that PPARgamma activation is at least partially responsible for the RARbeta2 transcription and maturation induction. In an in vivo mouse model of APL, CDDO derivative CDDO-methyl ester markedly enhanced ATRA-induced maturation and extended the survival of mice. In summary, these results provide rationale for the combined targeting of RAR and PPARgamma nuclear receptors in the therapy of APL.
Tabe
Yoko
Y
Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Konopleva
Marina
M
Kondo
Yutaka
Y
Contractor
Rooha
R
Tsao
Twee
T
Konoplev
Sergej
S
Shi
Yuexi
Y
Ling
Xiaoyang
X
Watt
Julie C
JC
Tsutsumi-Ishii
Yuko
Y
Ohsaka
Akimichi
A
Nagaoka
Isao
I
Issa
Jean-Pierre J
JP
Kogan
Scott C
SC
Andreeff
Michael
M
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006657:Histones / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D009539:Nicotinic Acids / Q000494:pharmacology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D047495:PPAR gamma / Q000187:drug effects*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000235:genetics; D020218:Response Elements / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014212:Tretinoin / Q000819:agonists / Q000494:pharmacology*
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000970:Antineoplastic Agents; D006657:Histones; D009539:Nicotinic Acids; D047495:PPAR gamma; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D013764:Tetrahydronaphthalenes; C082925:retinoic acid receptor beta; D014212:Tretinoin; D009828:Oleanolic Acid; C445068:bardoxolone methyl; C095104:LG 100268