Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)-->signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3.
The C-28 methyl ester of the oleane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) induces apoptosis of human cancer cells by disrupting redox balance and is in clinical trials. CDDO-Me contains alpha,beta-unsaturated carbonyl groups that form reversible adducts with thiol nucleophiles. The present studies show that CDDO-Me blocks interleukin-6 (IL-6)-induced and constitutive activation of the Janus-activated kinase 1 (JAK1) in cells. In support of a direct mechanism, CDDO-Me forms adducts with JAK1 at Cys(1077) in the kinase domain and inhibits JAK1 activity. In concert with these results, CDDO-Me blocked IL-6-induced and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Moreover, we show that CDDO-Me (a) binds directly to STAT3 by a mechanism dependent on the alkylation of Cys(259) and (b) inhibits the formation of STAT3 dimers. These findings indicate that CDDO-Me inhibits activation of the JAK1-->STAT3 pathway by forming adducts with both JAK1 and STAT3.
Ahmad
Rehan
R
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Raina
Deepak
D
Meyer
Colin
C
Kufe
Donald
D
D001710:Biotin / Q000378:metabolism; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D019281:Dimerization; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
D001710:Biotin; D015850:Interleukin-6; D053613:Janus Kinase 1; D009828:Oleanolic Acid; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C494086:STAT3 protein, human; C445068:bardoxolone methyl; C507904:JAK1 protein, human