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Deoxycholic acid mediates non-canonical EGFR-MAPK activation through the induction of calcium signaling in colon cancer cells.

Authors
  • Centuori, Sara M1
  • Gomes, Cecil J2
  • Trujillo, Jesse2
  • Borg, Jamie1
  • Brownlee, Joshua1
  • Putnam, Charles W3
  • Martinez, Jesse D4
  • 1 University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, United States. , (United States)
  • 2 Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85724, United States. , (United States)
  • 3 Department of Surgery, University of Arizona, Tucson, AZ 85724, United States. , (United States)
  • 4 University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, United States; Cell & Molecular Medicine, University of Arizona, Tucson, AZ 85724, United States. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Biochimica et Biophysica Acta
Publisher
Elsevier
Publication Date
Jul 01, 2016
Volume
1861
Issue
7
Pages
663–670
Identifiers
DOI: 10.1016/j.bbalip.2016.04.006
PMID: 27086143
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Obesity and a western diet have been linked to high levels of bile acids and the development of colon cancer. Specifically, increased levels of the bile acid deoxycholic acid (DCA), an established tumor promoter, has been shown to correlate with increased development of colorectal adenomas and progression to carcinoma. Herein we investigate the mechanism by which DCA leads to EGFR-MAPK activation, a candidate mechanism by which DCA may promote colorectal tumorigenesis. DCA treated colon cancer cells exhibited strong and prolonged activation of ERK1/2 when compared to EGF treatment alone. We also showed that DCA treatment prevents EGFR degradation as opposed to the canonical EGFR recycling observed with EGF treatment. Moreover, the combination of DCA and EGF treatment displayed synergistic activity, suggesting DCA activates MAPK signaling in a non-canonical manner. Further evaluation showed that DCA treatment increased intracellular calcium levels and CAMKII phosphorylation, and that blocking calcium with BAPTA-AM abrogated MAPK activation induced by DCA, but not by EGF. Finally we showed that DCA-induced CAMKII leads to MAPK activation through the recruitment of c-Src. Taken together, we demonstrated that DCA regulates MAPK activation through calcium signaling, an alternative mechanism not previously recognized in human colon cancer cells. Importantly, this mechanism allows for EGFR to escape degradation and thus achieve a constitutively active state, which may explain its tumor promoting effects. Copyright © 2016 Elsevier B.V. All rights reserved.

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