Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation.
We have previously published that 2 proven treatments for acute promyelocytic leukemia, As2O3 and retinoic acid, can be antagonistic in vitro. We now report that As2O3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize with the retinoid X receptor alpha (RXRalpha). As2O3 did not inhibit transactivation of the estrogen receptor or the glucocorticoid receptor, which do not heterodimerize with RXRalpha. We further show that As2O3 inhibits expression of several target genes of RXRalpha partners. Phosphorylation of RXRalpha has been reported to inhibit nuclear receptor signaling, and we show by in vivo labeling and phosphoamino acid detection that As2O3 phosphorylated RXRalpha in the N-terminal ABC region exclusively on serine residues. Consistent with our previous data implying a role for JNK in As2O3-induced apoptosis, we show that pharmacologic or genetic inhibition of JNK activation decreased As2O3-induced RXRalpha phosphorylation and blocked the effects of As2O3 on RXRalpha-mediated transcription. A mutational analysis indicated that phosphorylation of a specific serine residue, S32, was primarily responsible for inhibition of RXRalpha-mediated transcription. These data may provide some insight into the rational development of chemotherapeutic combinations involving As2O3 as well as into molecular mechanisms of arsenic-induced carcinogenesis resulting from environmental exposure.
Mann
Koren K
KK
Montréal Centre for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.
Padovani
Alessandra M S
AM
Guo
Qi
Q
Colosimo
April L
AL
Lee
Ho-Young
HY
Kurie
Jonathan M
JM
Miller
Wilson H
WH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D019556:COS Cells; D002274:Carcinogens, Environmental / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004781:Environmental Exposure / Q000009:adverse effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D001152:Arsenicals; D002274:Carcinogens, Environmental; D010087:Oxides; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D047490:Retinoid X Receptor alpha; D012694:Serine; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D000077237:Arsenic Trioxide