Abstract
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.
Highlights
Expressed in ovarian cancer-2/disabled 2 (DOC-2/ DAB2) is a potent growth inhibitor for prostate cancer cells by suppressing several mitogen-elicited mitogen-activated protein kinase (MAPK) pathway [1,2,3]
This could be important because DOC-2/ DAB2 is a large protein containing many other functional domains that are not fully characterized
From the structural/functional analysis of DOC-2/DAB2, we have shown that DOC-2/DAB2 can selectively bind to the Src homologue 3 (SH3) domain-containing proteins, such as growth factor receptor bound protein 2 (Grb2), c-Src, Fgr, and Nck but not to Crk or Spectrin [1, 2]
Summary
Expressed in ovarian cancer-2/disabled 2 (DOC-2/ DAB2) is a potent growth inhibitor for prostate cancer cells by suppressing several mitogen-elicited mitogen-activated protein kinase (MAPK) pathway [1,2,3]. Our data indicate that the prolinerich domain in the COOH terminus of DOC-2/DAB2 is the key functional domain responsible for this activity. DOC-2/DAB2 could be a potential therapeutic agent for prostate cancer. Recent development of cell-permeable peptide (CPP) as a delivery vehicle in. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). 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@ utsouthwestern.edu
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