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Role of heparin‐binding EGF‐related peptides in proliferation and apoptosis of activated ras ‐stimulated intestinal epithelial cells
Author(s) -
Zushi Shinichiro,
Shinomura Yasuhisa,
Kiyohara Tatsuya,
Miyazaki Yoshiji,
Tsutsui Shusaku,
Sugimachi Masamitsu,
Higashimoto Yoshifumi,
Kanayama Shuji,
Matsuzawa Yuji
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(19971210)73:6<917::aid-ijc26>3.0.co;2-#
Subject(s) - autocrine signalling , epidermal growth factor , biology , growth factor , cell growth , growth factor receptor inhibitor , apoptosis , tgf alpha , amphiregulin , paracrine signalling , microbiology and biotechnology , intestinal epithelium , signal transduction , cancer research , growth factor receptor , receptor , epithelium , biochemistry , genetics
The ras mutation is a common and critical step in carcinogenesis. Autocrine growth factors are also known to play an important role in cancer cell growth and transformation. However, the contribution of autocrine growth factors in regulation of proliferation and apoptosis of activated ras ‐stimulated intestinal epithelium is not fully understood. Therefore, we constructed activated ras ‐transfected intestinal epithelial cell clones (IEC‐ ras ) to examine the role of epidermal growth factor (EGF)‐related peptides in the behavior of IEC‐ ras. Overexpression of EGF family growth factors (transforming growth factor α, heparin‐binding EGF‐like growth factor, amphiregulin and betacellulin) and stronger phosphorylation of the EGF receptor was observed in IEC‐ ras compared with control cells. IEC‐ ras proliferated more rapidly than control cells, and a specific EGF receptor kinase inhibitor, AG1478, abolished the increased proliferation of IEC‐ ras. Heparitinase and chlorate also prevented increased proliferation of IEC‐ ras. Additionally, IEC‐ ras expressed more bcl‐2 and was more resistant to apoptosis induction by UV radiation and mitomycin C. AG1478 suppressed bcl‐2 expression and inhibited resistance to apoptosis of IEC‐ ras. Heparitinase and chlorate had effects similar to those of AG1478. Our data indicate that heparin‐binding EGF family growth factors play an important role in both increased proliferation and resistance to apoptosis of ras ‐stimulated intestinal epithelial cells. Int. J. Cancer 73:917–923, 1997. © 1997 Wiley‐Liss, Inc.