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J. Biol. Chem., Vol. 277, Issue 31, 27643-27650, August 2, 2002
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From the 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 tumors. 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 tumor 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 from that in normal cells. Our results
indicate that by targeting a growth factor-mediated survival signaling
pathway, BAD phosphorylation can be manipulated therapeutically to
induce apoptosis.
Activation of BAD by Therapeutic Inhibition of Epidermal
Growth Factor Receptor and Transactivation by Insulin-like Growth
Factor Receptor*
§,,,
,,§§
School of Biological Sciences, University of
Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, United
Kingdom, the Department of Surgery, University Hospital of South
Manchester, Nell Lane, Manchester M20 8LR, United Kingdom, the
** Ludwig Institute for Cancer Research/University College
London Breast Cancer Laboratory, Department of Surgery, 67-73
Riding House Street, London W1P 7LD, United Kingdom,
AstraZeneca Pharmaceuticals, Mereside,
Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom, and the
¶ Departments of Pathology and Medicine, Harvard Medical School,
Dana-Farber Cancer Institute, Boston, Massachusetts 02115
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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