Transformation of intestinal epithelial cells by chronic TGF-beta1 treatment results in downregulation of the type II TGF-beta receptor and induction of cyclooxygenase-2

Oncogene. 1999 Jan 28;18(4):855-67. doi: 10.1038/sj.onc.1202397.

Abstract

The precise role of TGF-beta in colorectal carcinogenesis is not clear. The purpose of this study was to determine the phenotypic alterations caused by chronic exposure to TGF-beta in non-transformed intestinal epithelial (RIE-1) cells. Growth of RIE-1 cells was inhibited by >75% following TGF-beta1 treatment for 7 days, after which the cells resumed a normal growth despite the presence of TGF-beta1. These 'TGF-beta-resistant' cells (RIE-Tr) were continuously exposed to TGF-beta for >50 days. Unlike the parental RIE cells, RIE-Tr cells lost contact inhibition, formed foci in culture, grew in soft agarose. RIE-Tr cells demonstrated TGF-beta-dependent invasive potential in an in vitro assay and were resistant to Matrigel and Na-butyrate-induced apoptosis. The RIE-Tr cells were also tumorigenic in nude mice. The transformed phenotype of RIE-Tr cells was associated with a 95% decrease in the level of the type II TGF-beta receptor (TbetaRII) protein, a 40-fold increase in cyclooxygenase-2 (COX-2) protein, and 5.9-fold increase in the production of prostacyclin. Most RIE-Tr subclones that expressed low levels of TbetaRII and high levels of COX-2 were tumorigenic. Those subclones that express abundant TbetaRII and low levels of COX-2 were not tumorigenic in nude mice. A selective COX-2 inhibitor inhibited RIE-Tr cell growth in culture and tumor growth in nude mice. The reduced expression of TbetaRII, increased expression of COX-2, and the ability to form colonies in Matrigel were all reversible upon withdrawal of exogenous TGF-beta1 for the RIE-Tr cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Count
  • Cell Division / drug effects
  • Cell Transformation, Neoplastic / chemically induced*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cyclooxygenase 2
  • Down-Regulation*
  • Drug Resistance
  • Enzyme Induction
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Intestines / cytology
  • Intestines / drug effects*
  • Isoenzymes / metabolism*
  • Phenotype
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Protein-Serine-Threonine Kinases
  • Rats
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Isoenzymes
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II