Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor receptor/Raf-1-dependent mechanism

Jung Hwan Yoon, Nathan W. Werneburg, Hajime Higuchi, Ali E. Canbay, Scott H Kaufmann, Cahit Akgul, Steven W. Edwards, Gregory James Gores

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Abstract

Bile acids have been implicated in biliary tract carcinogenesis, in part, by activating the epidermal growth factor receptor (EGFR). Overexpression of Mcl-1, a potent antiapoptotic protein of the Bcl-2 family, has also been reported in cholangiocarcinomas. Because receptor tyrosine kinases like EGFR may modulate antiapoptotic protein expression, we examined the hypothesis that bile acids modulate Mcl-1 expression levels via EGFR. Deoxycholate increased cellular Mcl-1 protein in a concentration-dependent manner. The deoxycholate-mediated increase of cellular Mcl-1 protein was blocked equally by EGFR tyrosine kinase inhibitors or an EGFR-neutralizing antibody. Although inhibition of mitogen-activated protein kinases did not attenuate the deoxycholate-associated increase in Mcl-1 protein, the Raf-1 inhibitor, BAY 37-9751, effectively blocked the cellular increase of this protein. Neither Mcl-1 transcriptional activity nor its mRNA stability was altered by deoxycholate treatment. However, Mcl-1 protein stability was increased by bile acid treatment, an effect duplicated by proteasome inhibition. Deoxycholate prolongation of Mcl-1 turnover was blocked by either EGFR inhibitors or the Raf-1 inhibitor. Whereas the deoxycholate-induced increase in Mcl-1 reduced Fas-mediated apoptosis, the Raf-1 inhibitor potentiated Fas apoptosis. Our results demonstrate that bile acids block Mcl-1 protein degradation via activation of an EGFR/Raf-1 cascade resulting in its cellular accumulation. Raf-1 inhibitors block this increase of Mcl-1 and render the cells more susceptible to apoptosis, a potential therapeutic strategy for cholangiocarcinomas.

Original languageEnglish (US)
Pages (from-to)6500-6505
Number of pages6
JournalCancer Research
Volume62
Issue number22
StatePublished - Nov 15 2002

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Yoon, J. H., Werneburg, N. W., Higuchi, H., Canbay, A. E., Kaufmann, S. H., Akgul, C., Edwards, S. W., & Gores, G. J. (2002). Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor receptor/Raf-1-dependent mechanism. Cancer Research, 62(22), 6500-6505.