RT Journal Article
SR Electronic
T1 Methyl 2-Cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) Decreases Specificity Protein (Sp) Transcription Factors and Inhibits Pancreatic Tumor Growth: Role of MicroRNA-27a
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.064451
DO 10.1124/mol.110.064451
A1 Indira Jutooru
A1 Gayathri Chadalapaka
A1 Maen Abdelrahim
A1 Md. Riyaz Basha
A1 Ismael Samudio
A1 Marina Konopleva
A1 Michael Andreeff
A1 Stephen H. Safe
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/05/20/mol.110.064451.abstract
AB The anticancer agent 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-Me) typically induce a broad spectrum of growth inhibitory, proapototic and antiangiogenic responses. Treatment of Panc1, Panc28 and L3.6pL pancreatic cancer cells with low μM concentrations of CDDO or CDDO-Me resulted in growth inhibition, induction of apoptosis, and downregulation of cyclin D1, survivin, vascular endothelial growth factor (VEGF) and its receptor (VEGFR2). RNA interference studies indicate that these repressed genes are regulated by specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4, and western blot analysis of lysates from pancreatic cancer cells treated with CDDO and CDDO-Me shows for the first time that both compounds decreased expression of Sp1, Sp3 and Sp4. Moreover, CDDO-Me (7.5 mg/kg/day) also inhibited pancreatic human L3.6pL tumor growth and downregulated Sp1, Sp3 and Sp4 in tumors using an orthotopic pancreatic cancer model. CDDO-Me also induced reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) in Panc1 and L3.6pL cells, and cotreatment with antioxidants (glutathione and dithiothreitol) blocked formation of ROS, reversed the loss of MMP, and also inhibited downregulation of Sp1, Sp3 and Sp4. Repression of Sp and Sp-dependent genes by CDDO-Me was due to downregulation of microRNA-27a and induction of ZBTB10, an Sp repressor, and these responses were also reversed by antioxidants. Thus, the anticancer activity of CDDO-Me is due, in part, to activation of ROS which in turn targets the microRNA-27a:ZBTB10-Sp transcription factor axis. This results in decreased expression of Sp-regulated genes, growth inhibition, induction of apoptosis, and antiangiogenic responses.The American Society for Pharmacology and Experimental Therapeutics