Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor

Andrew P. Gilmore, Anthony J. Valentijn, Pengbo Wang, Ann M. Ranger, Nigel Bundred, Michael J. O'Hare, Alan Wakeling, Stanley J. Korsmeyer, Charles H. Streuli

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)27643-27650
    Number of pages7
    JournalJournal of Biological Chemistry
    Volume277
    Issue number31
    DOIs
    Publication statusPublished - 2 Aug 2002

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