Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation.

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Mann KK, Padovani AM, Guo Q, Colosimo AL, Lee HY, Kurie JM, Miller WH Jr

Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation.

J Clin Invest. 2005 Oct;115(10):2924-33. Epub 2005 Sep 22.

PubMed ID

16184197 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Arsenic trioxide	Cytochrome P450 3A4	Protein	Humans	Unknown	Inhibitor	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Tretinoin	Approved Investigational Nutraceutical	CEBPE	1053	upregulated	Tretinoin results in increased expression of CEBPE mRNA	14q11.2
Tretinoin	Approved Investigational Nutraceutical	RARB	5915	upregulated	Tretinoin results in increased expression of RARB mRNA	3p24.2
Cholecalciferol	Approved Nutraceutical	CYP24A1	1591	upregulated	Cholecalciferol results in increased expression of CYP24A1 mRNA	20q13.2

Pharmaco-proteomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Rifampicin	Approved	CYP3A4	1576	increased	Rifampin results in increased expression of CYP3A4 protein	7q22.1
Rifampicin	Approved	CYP3A4	1576	increased	Rifampin results in increased expression of CYP3A4 protein	7q22.1
Rifampicin	Approved	CYP3A4	1576	increased	Rifampin results in increased expression of CYP3A4 protein	7q22.1