title: Deoxycholic acid mediates non-canonical EGFR-MAPK activation through the induction of calcium signaling in colon cancer cells.
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.
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, United States.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Centuori
authors.affiliation: Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85724, United States.
authors.forename: Cecil J
authors.initials: CJ
authors.lastname: Gomes
authors.affiliation: Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85724, United States.
authors.forename: Jesse
authors.initials: J
authors.lastname: Trujillo
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, United States.
authors.forename: Jamie
authors.initials: J
authors.lastname: Borg
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Brownlee
authors.affiliation: Department of Surgery, University of Arizona, Tucson, AZ 85724, United States.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Putnam
authors.affiliation: 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: jmartinez@uacc.arizona.edu.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Martinez
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D003840:Deoxycholic Acid / Q000494:pharmacology*; D004357:Drug Synergism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D003840:Deoxycholic Acid; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium
keywords: Bile acids; Calcium signaling; Colon cancer; DCA; EGFR activation