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Amphiregulin antisense oligonucleotide inhibits the growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptor‐targeted therapy
Author(s) -
Funatomi Hitoshi,
Itakura Jun,
Ishiwata Toshiyuki,
Pastan Ira,
Thompson Stewart A.,
Johnson Gibbes R.,
Korc Murray
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19970729)72:3<512::aid-ijc21>3.0.co;2-c
Subject(s) - amphiregulin , autocrine signalling , epidermal growth factor receptor , epidermal growth factor , cancer research , pancreatic cancer , growth factor , biology , cetuximab , tgf alpha , cancer cell , receptor , medicine , endocrinology , cancer , immunology , monoclonal antibody , biochemistry , antibody
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. Int. J. Cancer 72:512–517, 1997. © 1997 Wiley‐Liss, Inc.