Amphiregulin antisense oligonucleotide inhibits the growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptor-targeted therapy

Hitoshi Funatomi, Jun Itakura, Toshiyuki Ishiwata, Ira Pastan, Stewart A. Thompson, Gibbes R. Johnson, Murray Korc

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Human pancreatic cancers overexpress the epidermal growth factor (EGF) receptor (EGFR) and all 5 ligands that bind to this receptor, including amphiregulin. It is not known, however, whether amphiregulin contributes in an autocrine manner to enhance pancreatic cancer cell growth. Therefore, we used an amphiregulin antisense oligonucleotide (AR-AS) to suppress amphiregulin expression in T3M4 human pancreatic cancer cells. These cells express high levels of EGFR and amphiregulin. AR-AS abolished amphiregulin immunoreactivity in T3M4 cells, decreased amphiregulin release into the medium and inhibited cell growth in a dose-dependent manner. Exogenous amphiregulin reversed AR-AS-mediated growth inhibition. A random oligonucleotide (AR-R) did not alter either cell growth or cellular amphiregulin immunoreactivity. AR-AS also increased cellular EGFR protein levels and enhanced the growth-inhibitory actions of TP40, a chimeric protein consisting of transforming growth factor-α coupled to pseudomonas exotoxin that internalizes into cells via EGFR. These findings indicate that there is an important EGFR/amphiregulin autocrine loop in T3M4 cells and raise the possibility that modalities aimed at abrogating amphiregulin action may prove useful in pancreatic cancer, especially when used in conjunction with EGFR-targeted therapy.

Original languageEnglish (US)
Pages (from-to)512-517
Number of pages6
JournalInternational Journal of Cancer
Volume72
Issue number3
DOIs
StatePublished - 1997
Externally publishedYes

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Antisense Oligonucleotides
Pancreatic Neoplasms
Epidermal Growth Factor Receptor
Growth
Therapeutics
Amphiregulin
Exotoxins
Transforming Growth Factors
Pseudomonas
Oligonucleotides
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Amphiregulin antisense oligonucleotide inhibits the growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptor-targeted therapy. / Funatomi, Hitoshi; Itakura, Jun; Ishiwata, Toshiyuki; Pastan, Ira; Thompson, Stewart A.; Johnson, Gibbes R.; Korc, Murray.

In: International Journal of Cancer, Vol. 72, No. 3, 1997, p. 512-517.

Research output: Contribution to journalArticle

Funatomi, Hitoshi ; Itakura, Jun ; Ishiwata, Toshiyuki ; Pastan, Ira ; Thompson, Stewart A. ; Johnson, Gibbes R. ; Korc, Murray. / Amphiregulin antisense oligonucleotide inhibits the growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptor-targeted therapy. In: International Journal of Cancer. 1997 ; Vol. 72, No. 3. pp. 512-517.
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