Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor.
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.
Gilmore
Andrew P
AP
School of Biological Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom. agilmore@man.ac.uk
Valentijn
Anthony J
AJ
Wang
Pengbo
P
Ranger
Ann M
AM
Bundred
Nigel
N
O'Hare
Michael J
MJ
Wakeling
Alan
A
Korsmeyer
Stanley J
SJ
Streuli
Charles H
CH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D000077156:Gefitinib; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011247:Pregnancy; D011799:Quinazolines / Q000494:pharmacology*; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D051025:bcl-Associated Death Protein
D000970:Antineoplastic Agents; C494820:Bad protein, mouse; D002352:Carrier Proteins; D011799:Quinazolines; D017451:Receptors, Somatomedin; D051025:bcl-Associated Death Protein; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000077156:Gefitinib