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Departments of Internal Medicine and Pathology, John D. Dingell Veterans Affairs Medical Center, Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, Michigan

Requests for reprints: Adhip P.N. Majumdar, Research Service, Room B 4238, John D. Dingell Veterans Affairs Medical Center, 4646 John R, Detroit, MI 48201. Phone: 313-576-1000, ext. 4460; Fax: 313-576-1112. E-mail: a.majumdar{at}wayne.edu

Interference with the activation of growth factor receptors, specifically epidermal growth factor receptor (EGFR), represents a promising strategy for the development of novel and selective anticancer therapies. We reported that EGFR-related peptide (ERRP), a recently isolated negative regulator of EGFR, could be a potential therapeutic agent for colorectal cancer. To determine whether ERRP could potentially be a therapeutic agent for prostate carcinoma, we examined the effect of recombinant ERRP on the growth of the prostate cancer cell line PC-3 in vitro. Events of the EGFR signal transduction pathways were also examined. ERRP caused a marked inhibition of cell growth in a dose- and time-dependent manner and also induced apoptosis. The latter was evidenced by increased number of apoptotic cells, activation of caspase-3, and cleavage of poly(ADP-ribose)polymerase. The transforming growth factor-–induced stimulation of cell growth and activation of EGFR was also inhibited by ERRP. These changes were accompanied by a concomitant attenuation of activation of Akt and mitogen-activated protein kinases as well as basal and transforming growth factor-–induced activation of nuclear factor-B. Inhibition of EGFR activation by ERRP could be partly attributed to increased sequestration of EGFR ligands. In summary, our data show that ERRP inhibits the growth of prostate cancer cells by attenuating EGFR signaling processes. ERRP could potentially be an effective therapeutic agent for prostate cancer.

Key Words: EGF receptor • PC-3 cells • growth • prostate cancer • apoptosis • EGFR signal transduction

Grant support: NIH/National Institute on Aging grant RO1 AG14343 and Department of Veterans Affairs VA Merit Review (A.P.N. Majumdar).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/18/04; revised 9/ 3/04; accepted 10/ 6/04.