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Inhibition of Mitogen-Elicited Signal Transduction and Growth in Prostate Cancer with a Small Peptide Derived from the Functional Domain of DOC-2/DAB2 Delivered by a Unique Vehicle

Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Requests for reprints: Jer-Tsong Hsieh, Department of Urology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9110. Phone: 214-648-3988; Fax: 214-648-8786; E-mail: jt.hsieh{at}utsouthwestern.edu.

Differentially expressed in ovarian cancer-2/disabled 2 (DOC-2/DAB2) protein, often lost in prostate cancer and other cancer types, is a part of homeostatic machinery in normal prostate epithelium. DOC-2/DAB2 modulates mitogen-elicited mitogen-activated protein kinase (MAPK) signal transduction by sequestering several adaptor or effector molecules, such as growth factor receptor bound protein 2 and c-Src. We have shown that the proline-rich sequence in DOC-2/DAB2 is the key functional domain for this action. In this study, we further synthesized peptide based on the functional proline-rich domain and examined its biological function in prostate cancer using cell-permeable peptide (CPP) as a delivery system. From screening of several CPPs in prostate cancer cell lines, a polyarginine peptide (R11) seemed to be the best delivery vehicle because of its highly efficient uptake. In addition, we also observed a similar in vitro half-life and cellular location of R11 in four different prostate cancer cell lines. By conjugating a proline-rich sequence (PPL) or control sequence (AAL) derived from DOC-2/DAB2 to the COOH terminus of R11, we showed that R11PPL but not R11 or R11AAL was able to suppress either serum- or androgen-induced cell proliferation in prostate cancer cells without endogenous DOC-2/DAB2 expression. Consistently, the activation status of MAPK elicited by these mitogens was significantly inhibited by R11PPL but not by R11AAL or R11. Taken together, we conclude that a functional peptide derived from proline-rich domain in DOC-2/DAB2 has growth-inhibitory activity as its native protein, and CPP seems to be an efficient delivery system in prostate cancer cells. (Cancer Res 2006; 66(18): 8954-8)