title: Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids.
abstract: Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how they mediate this effect is unclear. In this study, we offer evidence of a mechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface protease TACE/ADAM-17. Specifically, we show that AREG participates in DCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE and AREG, but not TGF-α, were overexpressed in both colorectal cancer and PDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDAC cells to DCA resulted in colocalization of Src and TACE to the cell membrane, resulting in AREG-dependent activation of EGFR, mitogen-activated protein kinase (MAPK), and STAT3 signaling. Src or TACE inhibition was sufficient to attenuate DCA-induced AREG, but not TGF-α shedding. We also examined a role for the BA transporter TGR5 in DCA-mediated EGFR and STAT3 signaling. RNA interference-mediated silencing of TGR5 or AREG inhibited DCA-induced EGFR, MAPK, and STAT3 signaling, blunted cyclin D1 expression and cell-cycle progression, and attenuated DCA-induced colorectal cancer or PDAC tumorigenicity. Together, our findings define an AREG-dependent signaling pathway that mediates the oncogenic effects of secondary BAs in gastrointestinal cancers, the targeting of which may enhance therapeutic responses in their treatment.
authors: Authors' Affiliations: Departments of Surgery, Cancer Biology, Pathology, and Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky; and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors: Nagaraj S
authors: NS
authors: Nagathihalli
authors: Yugandhar
authors: Y
authors: Beesetty
authors: Wooin
authors: W
authors: Lee
authors: M Kay
authors: MK
authors: Washington
authors: Xi
authors: X
authors: Chen
authors: A Craig
authors: AC
authors: Lockhart
authors: Nipun B
authors: NB
authors: Merchant
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D066258:Amphiregulin; D001647:Bile Acids and Salts / Q000633:toxicity*; D019938:Cyclin D1 / Q000235:genetics; D003840:Deoxycholic Acid / Q000633:toxicity; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000502:physiology; D005770:Gastrointestinal Neoplasms / Q000139:chemically induced*; D006023:Glycoproteins / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D010179:Pancreas / Q000378:metabolism; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D001647:Bile Acids and Salts; C530104:CCND1 protein, human; D066255:EGF Family of Proteins; C473772:GPBAR1 protein, human; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016211:Transforming Growth Factor alpha; D003840:Deoxycholic Acid; D019938:Cyclin D1; D066246:ErbB Receptors; D019061:src-Family Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human