Novel prostate-specific promoter derived from PSA and PSMA enhancers.
The expression of prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA), two well characterized marker proteins, remains highly active in the hormone refractory stage of prostate cancer. In this study, an artificial chimeric enhancer (PSES) composed of two modified regulatory elements controlling the expression of PSA and PSMA genes was tested for its promoter activity and tissue specificity using the reporter system. As a result, this novel PSES promoter remained silent in PSA- and PSMA-negative prostate and non-prostate cancer cell lines, but mediated high levels of luciferase in PSA- and PSMA-expressing prostate cancer cell lines in the presence and absence of androgen. To determine whether PSES could be used for in vivo gene therapy of prostate cancer, a recombinant adenovirus, Ad-PSES-luc, was constructed. Luciferase activity in prostate cancer cell lines mediated by Ad-PSES-luc was 400- to 1000-fold higher than in several other non-prostate cell lines, suggesting the high tissue-specificity of the PSES promoter in an adenoviral vector. Finally, recombinant virus Ad-PSES-luc was injected into mice to evaluate the tissue-discriminatory promoter activity in an experimental animal. Unlike Ad-CMV-luc, the luciferase activity from systemic injection of Ad-PSES-luc was fairly low in all major organs. However, when injected into prostate, Ad-PSES-luc drove high luciferase activity almost exclusively in prostate and not in other tissues. Our results demonstrated the potential use of PSES for the treatment of androgen-independent prostate cancer patients.
Lee
Sang-Jin
SJ
Department of Urology, Indiana University, Indianapolis, Indiana 46202, USA.
Kim
Hong-Sup
HS
Yu
Rong
R
Lee
KangRyul
K
Gardner
Thomas A
TA
Jung
Chaeyong
C
Jeng
Meei-Huey
MH
Yeung
Fan
F
Cheng
Liang
L
Kao
Chinghai
C
D000256:Adenoviridae / Q000235:genetics; D000954:Antigens, Surface; D001483:Base Sequence; D002268:Carboxypeptidases / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005822:Genetic Vectors; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics*; D011995:Recombination, Genetic
D000954:Antigens, Surface; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen