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

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.

• Authors: Jung-Hwan Yoon, Nathan W Werneburg, Hajime Higuchi, Ali E Canbay, Scott H Kaufmann, Cahit Akgul, Steven W Edwards, Gregory J Gores
• Journal: Cancer research (Cancer Res) Vol. 62 Issue 22 Pg. 6500-5 (Nov 15 2002) ISSN: 0008-5472 [Print] United States
• PMID: 12438243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• Deoxycholic Acid
• ErbB Receptors
• Proto-Oncogene Proteins c-raf

Topics

• Apoptosis (drug effects, physiology)
• Cholangiocarcinoma (metabolism)
• Deoxycholic Acid (pharmacology)
• ErbB Receptors (antagonists & inhibitors, physiology)
• Humans
• MAP Kinase Signaling System (drug effects, physiology)
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-raf (antagonists & inhibitors, physiology)
• RNA, Messenger (biosynthesis, genetics)
• Transcription, Genetic (drug effects)
• Tumor Cells, Cultured