Ribozyme-mediated inhibition of survivin expression increases spontaneous and drug-induced apoptosis and decreases the tumorigenic potential of human prostate cancer cells.
Survivin is a member of the inhibitor of apoptosis protein (IAP) family, which has been implicated in inhibition of apoptosis and control of mitotic progression. The finding that survivin is overexpressed in most human tumors but absent in normal adult tissues has led to the proposal of survivin as a promising therapeutic target for anticancer therapies. We decided to evaluate the effects of a ribozyme-based strategy for survivin inhibition in androgen-independent human prostate cancer cells. We constructed a Moloney-based retroviral vector expressing a ribozyme targeting the 3' end of the CUA(110) triplet in survivin mRNA, encoded as a chimeric RNA within adenoviral VA1 RNA. Polyclonal cell populations obtained by infection with the retroviral vector of two androgen-independent human prostate cancer cell lines (DU145 and PC-3) were selected for the study. Ribozyme-expressing prostate cancer cells were characterized by a significant reduction of survivin expression compared to parental cells transduced with a control ribozyme; the cells became polyploid, underwent caspase-9-dependent apoptosis and showed an altered pattern of gene expression, as detected by oligonucleotide array analysis. Survivin inhibition also increased the susceptibility of prostate cancer cells to cisplatin-induced apoptosis and prevented tumor formation when cells were xenografted in athymic nude mice. These findings suggest that manipulation of the antiapoptotic survivin pathway may provide a novel approach for the treatment of androgen-independent prostate cancer.
Pennati
Marzia
M
Dipartimento di Oncologia Sperimentale, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy.
Binda
Mara
M
Colella
Gennaro
G
Zoppe'
Monica
M
Folini
Marco
M
Vignati
Sara
S
Valentini
Alessandra
A
Citti
Lorenzo
L
De Cesare
Michelandrea
M
Pratesi
Graziella
G
Giacca
Mauro
M
Daidone
Maria Grazia
MG
Zaffaroni
Nadia
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020029:Base Pairing; D001483:Base Sequence; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002945:Cisplatin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016337:RNA, Catalytic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D000077022:Survivin; D014161:Transduction, Genetic
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016337:RNA, Catalytic; D000077022:Survivin; D002945:Cisplatin