The long-term goal is to develop effective strategies for treating hormone-refractory (HR) prostate cancer (PCa). To accomplish this goal, the molecular mechanism by which advanced PCa cells escape from androgen requirement will be elucidated. Preliminary results showed that cellular prostatic acid phosphatase (cPAcP) and ErbB-2/HER-2/neu are involved in regulating androgen-stimulated cell proliferation. Decreased cPAcP correlates with androgen-independent (Al) growth of PCa cells, corroborating clinical phenomena. Further, p66Shc, an adaptor protein of ErbB-2, is elevated in PCa specimens and Al high passage (HP) LNCaP and MDA PCa2B cells. The working hypothesis is that aberrant ErbB-2 signaling, via p66Shc, represents one of functional pathways involving in hormone-refractory growth of PCa cells.
The specific aims are: 1. To determine the role of ErbB-2 in Al cell proliferation. This will be done by knocking down cPAcP expression with siRNA in androgen-sensitive (AS) low passage (LP) LNCaP and MDA PCa2b cells and analyze its effect on ErbB-2 activation and Al cell growth. Inhibition of cPAcP activity can also be done by transfecting LP cells with a cDNA encoding a negative mutant of cPAcP or culturing them in PAcP inhibitor. Al cell growth will also be examined in ErbB-2-knocked down cells by siRNA. Al phenotype will be confirmed in xenograft animals. The interaction between cPAcP and ErbB-2 will be determined by identifying the dephosphorylation sites. The mechanism by which butyrate up-regulates PAcP expression will be delineated. 2. To analyze p66Shc involvement in Al PCa cell proliferation. To elevate p66Shc expression, LP cells will be transfected with p66Shc cDNA and then androgen independence of transfected cells will be examined in culture and xenograft animals. Conversely, p66Shc will be knocked down by siRNA in HP cells and then androgen independence of those cells will be determined. The signaling pathway by which p66Shc up-regulates cell growth will be delineated. The mechanism by which p66Shc is elevated in Al cells will be investigated. 3. To correlate in vitro findings with clinical significance. The expression of p66Shc and cPAcP will be analyzed by immunohistochemistry staining of clinical archival specimens. The intensity and the extent of staining will be semi-quantified for calculating a composite score, which will be correlated with clinico-pathological progression of PCa, including HR PCa. ? ? ? ? ? ? ?
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