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Papers In Press, published online ahead of print May 13, 2002
School of Biological Sciences, University of Manchester, Manchester M13 9PT
Corresponding Author: agilmore{at}man.ac.uk
Novel cancer chemotherapeutics are required to induce apoptosis by activating pro-apoptotic proteins. Both epidermal growth factor (EGF) and insulin-like growth factor (IGF) provide potent survival stimuli in many epithelia, and activation of their receptors is commonly observed in solid human tumours. Here we demonstrate that blockade of the EGF receptor by a new drug in phase III clinical trails for cancer, ZD1839, potently induces apoptosis in mammary epithelial cell lines and primary cultures, as well as in a primary pleural effusion from a breast cancer patient. We identified the mechanism of apoptosis induction by ZD1839. We showed that it prevents cell survival by activating the pro-apoptotic protein, BAD. Moreover, we demonstrate that IGF transactivates the EGF receptor, and that ZD1839 blocks IGF-mediated phosphorylation of MAPK and BAD. Many cancer therapies kill tumour cells by inducing apoptosis as a consequence of targeting DNA, however the threshold at which apoptosis can be triggered through DNA damage is often different to normal cells. Our results indicate that by targeting a growth factor mediated survival signalling pathway, BAD phosphorylation can be manipulated therapeutically to induce apoptosis.
J. Biol. Chem, 10.1074/jbc.M108863200
Submitted on September 13, 2001
Revised on April 4, 2002
Accepted on May 13, 2002
Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin like growth factor receptor
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