Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR

Rebecca Feldman, Jesse D Martinez

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Ursodeoxycholic acid (UDCA) has been shown to prevent colon tumorigenesis in animal models and in humans. In vitro work indicates that this bile acid can suppress cell growth and mitogenic signaling suggesting that UDCA may be an anti-proliferative agent. However, the mechanism by which UDCA functions is unclear. Previously we showed that bile acids may alter cellular signaling by acting at the plasma membrane. Here we utilized EGFR as a model membrane receptor and examined the effects that UDCA has on its functioning. We found that UDCA promoted an interaction between EGFR and caveolin-1 and this interaction enhanced UDCA-mediated suppression of MAP kinase activity and cell growth. Importantly, UDCA treatment led to recruitment of the ubiquitin ligase, c-Cbl, to the membrane, ubiquitination of EGFR, and increased receptor degradation. Moreover, suppression of c-Cbl activity abrogated UDCA's growth suppression activities suggesting that receptor ubiquitination plays an important role in UDCA's biological activities. Taken together these results suggest that UDCA may act to suppress cell growth by inhibiting the mitogenic activity of receptor tyrosine kinases such as EGFR through increased receptor degradation.

Original languageEnglish (US)
Pages (from-to)1387-1394
Number of pages8
JournalBBA - Molecular Cell Research
Volume1793
Issue number8
DOIs
StatePublished - Aug 2009

Fingerprint

Caveolin 1
Ursodeoxycholic Acid
Growth
Ubiquitination
Bile Acids and Salts
Membranes
Receptor Protein-Tyrosine Kinases
Ligases
Ubiquitin
Colon
Carcinogenesis
Phosphotransferases
Animal Models
Cell Membrane

Keywords

  • Bile acid
  • c-Cbl
  • Chemoprevention
  • Colon cancer
  • Endocytosis

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR. / Feldman, Rebecca; Martinez, Jesse D.

In: BBA - Molecular Cell Research, Vol. 1793, No. 8, 08.2009, p. 1387-1394.

Research output: Contribution to journalArticle

@article{036030e3a55f446e888ec98b468b0b64,
title = "Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR",
abstract = "Ursodeoxycholic acid (UDCA) has been shown to prevent colon tumorigenesis in animal models and in humans. In vitro work indicates that this bile acid can suppress cell growth and mitogenic signaling suggesting that UDCA may be an anti-proliferative agent. However, the mechanism by which UDCA functions is unclear. Previously we showed that bile acids may alter cellular signaling by acting at the plasma membrane. Here we utilized EGFR as a model membrane receptor and examined the effects that UDCA has on its functioning. We found that UDCA promoted an interaction between EGFR and caveolin-1 and this interaction enhanced UDCA-mediated suppression of MAP kinase activity and cell growth. Importantly, UDCA treatment led to recruitment of the ubiquitin ligase, c-Cbl, to the membrane, ubiquitination of EGFR, and increased receptor degradation. Moreover, suppression of c-Cbl activity abrogated UDCA's growth suppression activities suggesting that receptor ubiquitination plays an important role in UDCA's biological activities. Taken together these results suggest that UDCA may act to suppress cell growth by inhibiting the mitogenic activity of receptor tyrosine kinases such as EGFR through increased receptor degradation.",
keywords = "Bile acid, c-Cbl, Chemoprevention, Colon cancer, Endocytosis",
author = "Rebecca Feldman and Martinez, {Jesse D}",
year = "2009",
month = "8",
doi = "10.1016/j.bbamcr.2009.05.003",
language = "English (US)",
volume = "1793",
pages = "1387--1394",
journal = "Biochimica et Biophysica Acta - Molecular Cell Research",
issn = "0167-4889",
publisher = "Elsevier",
number = "8",

}

TY - JOUR

T1 - Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR

AU - Feldman, Rebecca

AU - Martinez, Jesse D

PY - 2009/8

Y1 - 2009/8

N2 - Ursodeoxycholic acid (UDCA) has been shown to prevent colon tumorigenesis in animal models and in humans. In vitro work indicates that this bile acid can suppress cell growth and mitogenic signaling suggesting that UDCA may be an anti-proliferative agent. However, the mechanism by which UDCA functions is unclear. Previously we showed that bile acids may alter cellular signaling by acting at the plasma membrane. Here we utilized EGFR as a model membrane receptor and examined the effects that UDCA has on its functioning. We found that UDCA promoted an interaction between EGFR and caveolin-1 and this interaction enhanced UDCA-mediated suppression of MAP kinase activity and cell growth. Importantly, UDCA treatment led to recruitment of the ubiquitin ligase, c-Cbl, to the membrane, ubiquitination of EGFR, and increased receptor degradation. Moreover, suppression of c-Cbl activity abrogated UDCA's growth suppression activities suggesting that receptor ubiquitination plays an important role in UDCA's biological activities. Taken together these results suggest that UDCA may act to suppress cell growth by inhibiting the mitogenic activity of receptor tyrosine kinases such as EGFR through increased receptor degradation.

AB - Ursodeoxycholic acid (UDCA) has been shown to prevent colon tumorigenesis in animal models and in humans. In vitro work indicates that this bile acid can suppress cell growth and mitogenic signaling suggesting that UDCA may be an anti-proliferative agent. However, the mechanism by which UDCA functions is unclear. Previously we showed that bile acids may alter cellular signaling by acting at the plasma membrane. Here we utilized EGFR as a model membrane receptor and examined the effects that UDCA has on its functioning. We found that UDCA promoted an interaction between EGFR and caveolin-1 and this interaction enhanced UDCA-mediated suppression of MAP kinase activity and cell growth. Importantly, UDCA treatment led to recruitment of the ubiquitin ligase, c-Cbl, to the membrane, ubiquitination of EGFR, and increased receptor degradation. Moreover, suppression of c-Cbl activity abrogated UDCA's growth suppression activities suggesting that receptor ubiquitination plays an important role in UDCA's biological activities. Taken together these results suggest that UDCA may act to suppress cell growth by inhibiting the mitogenic activity of receptor tyrosine kinases such as EGFR through increased receptor degradation.

KW - Bile acid

KW - c-Cbl

KW - Chemoprevention

KW - Colon cancer

KW - Endocytosis

UR - http://www.scopus.com/inward/record.url?scp=67651119898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651119898&partnerID=8YFLogxK

U2 - 10.1016/j.bbamcr.2009.05.003

DO - 10.1016/j.bbamcr.2009.05.003

M3 - Article

C2 - 19446582

AN - SCOPUS:67651119898

VL - 1793

SP - 1387

EP - 1394

JO - Biochimica et Biophysica Acta - Molecular Cell Research

JF - Biochimica et Biophysica Acta - Molecular Cell Research

SN - 0167-4889

IS - 8

ER -