Novel mechanistic insights into ectodomain shedding of egfr ligands amphiregulin and TGF-α

Impact on gastrointestinal cancers driven by secondary bile acids

Nagaraj Nagathihalli, Yugandhar Beesetty, Wooin Lee, M. Kay Washington, Xi Chen, Albert Lockhart, Nipun Merchant

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how theymediate this effect is unclear. In this study, we offer evidence of amechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface proteaseTACE/ADAM-17. Specifically, weshowthatAREGparticipates inDCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE andAREG, but notTGF-α,were overexpressed in both colorectal cancer andPDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDACcells toDCAresulted in colocalization of Src andTACE 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-a 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.

Original languageEnglish (US)
Pages (from-to)2062-2072
Number of pages11
JournalCancer Research
Volume74
Issue number7
DOIs
StatePublished - Apr 1 2014
Externally publishedYes

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Gastrointestinal Neoplasms
Deoxycholic Acid
Bile Acids and Salts
Colorectal Neoplasms
Ligands
Mitogen-Activated Protein Kinases
Cell Cycle
Adenocarcinoma
Cyclin D1
RNA Interference
Cell Membrane
Amphiregulin
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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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 theymediate this effect is unclear. In this study, we offer evidence of amechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface proteaseTACE/ADAM-17. Specifically, weshowthatAREGparticipates inDCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE andAREG, but notTGF-α,were overexpressed in both colorectal cancer andPDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDACcells toDCAresulted in colocalization of Src andTACE 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-a 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.",
author = "Nagaraj Nagathihalli and Yugandhar Beesetty and Wooin Lee and Washington, {M. Kay} and Xi Chen and Albert Lockhart and Nipun Merchant",
year = "2014",
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doi = "10.1158/0008-5472.CAN-13-2329",
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TY - JOUR

T1 - Novel mechanistic insights into ectodomain shedding of egfr ligands amphiregulin and TGF-α

T2 - Impact on gastrointestinal cancers driven by secondary bile acids

AU - Nagathihalli, Nagaraj

AU - Beesetty, Yugandhar

AU - Lee, Wooin

AU - Washington, M. Kay

AU - Chen, Xi

AU - Lockhart, Albert

AU - Merchant, Nipun

PY - 2014/4/1

Y1 - 2014/4/1

N2 - Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how theymediate this effect is unclear. In this study, we offer evidence of amechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface proteaseTACE/ADAM-17. Specifically, weshowthatAREGparticipates inDCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE andAREG, but notTGF-α,were overexpressed in both colorectal cancer andPDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDACcells toDCAresulted in colocalization of Src andTACE 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-a 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.

AB - Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how theymediate this effect is unclear. In this study, we offer evidence of amechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface proteaseTACE/ADAM-17. Specifically, weshowthatAREGparticipates inDCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE andAREG, but notTGF-α,were overexpressed in both colorectal cancer andPDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDACcells toDCAresulted in colocalization of Src andTACE 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-a 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.

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DO - 10.1158/0008-5472.CAN-13-2329

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