Modulation of multidrug resistance in cancer cells by the E3 ubiquitin ligase seven-in-absentia homologue 1

The Journal of Pathology
M LiuJ Zhou

Abstract

Seven-in-absentia homologue 1 (Siah1) is an E3 ubiquitin ligase that regulates the ubiquitination and proteasome-dependent degradation of a number of proteins. Here we report that Siah1 modulates multidrug resistance 1 (MDR1)/P-glycoprotein-mediated drug resistance in the cancer cell lines examined. Siah1, but not its ligase-dead mutant, down-regulates MDR1/P-glycoprotein and sensitizes the multidrug-resistant cells to chemotherapeutic agents. Mechanistically, Siah1 does not promote P-glycoprotein degradation but decreases its expression transcriptionally by promoting c-Jun transcription factor binding to the activator protein 1 (AP1) site in the MDR1 promoter. Moreover, Siah1 triggers c-Jun NH2-terminal kinase (JNK) activation, leading to enhanced phosphorylation of c-Jun, and the JNK/c-Jun signalling axis is critical for Siah1 to down-regulate MDR1/P-glycoprotein expression. These findings demonstrate a previously unidentified role for Siah1 in regulating MDR1/P-glycoprotein expression through the JNK/c-Jun pathway.

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Citations

Oct 6, 2012·Leukemia·O H KrämerS K Knauer
Nov 19, 2009·Drug Design, Development and Therapy·Gerald F DaviesTroy A A Harkness
Sep 1, 2008·Expert Review of Clinical Pharmacology·Guillaume DumaisPatrick du Souich
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Sep 10, 2014·PloS One·Anupriya GopalsamyKunchithapadam Swaminathan
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Oct 25, 2016·Biochimica Et Biophysica Acta. General Subjects·Qi ZhangYufeng Tong

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