Adenovirus-mediated inhibition of survivin expression sensitizes human prostate cancer cells to paclitaxel in vitro and in vivo.
BACKGROUND
Improvements in the response rates to chemotherapy would represent an important advancement in the care of patients with metastatic prostate cancer. There is accumulating evidence that Survivin, a member of the inhibitor of apoptosis (IAP) family, is associated with both cancer progression and drug resistance. The purpose of this study is to investigate the role of Survivin in paclitaxel-resistance and whether the targeting of Survivin sensitizes prostate cancer cells to paclitaxel.


METHODS
Human prostate cell lines PC-3, DU-145, and LNCaP were infected with replication-deficient adenoviruses encoding either wild-type Survivin [pAd-S(WT)], to examine Survivin overexpression effects, or a phosphorylation-defective Survivin Thr34 --> Ala dominant negative mutant [pAd-S(T34A)], to examine Survivin inactivation effects. The effects of wild-type or mutant Survivin on spontaneous and paclitaxel-induced apoptosis were investigated both in vitro and in vivo.


RESULTS
Forced overexpression of wild-type Survivin with pAd-S(WT) increased resistance to paclitaxel in all cell lines, both in vitro and in vivo. Inhibition of Survivin using pAd-S(T34A) resulted in a significant increase in the rate of spontaneous and paclitaxel-induced apoptosis in all cell lines, both in vitro and in vivo. This effect was abolished by co-treatment with VAD-CHO (Calbiochem, San Diego, CA), a pan-caspase inhibitor, indicating that Survivin normally mediates resistance to paclitaxel through suppression of caspase-mediated apoptosis.


CONCLUSIONS
Survivin mediates paclitaxel-resistance in prostate cancer cells. The inhibition of Survivin sensitizes prostate cancer cells to paclitaxel-induced apoptosis through a caspase-dependant mechanism in vitro and in vivo.
Zhang
Min
M
Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School Boston, Massachusetts 02114, USA.
Mukherjee
Neelanjan
N
Bermudez
R Scott
RS
Latham
Douglas E
DE
Delaney
Meaghan A
MA
Zietman
Anthony L
AL
Shipley
William U
WU
Chakravarti
Arnab
A
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009363:Neoplasm Proteins; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077022:Survivin; D015854:Up-Regulation / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D020169:Caspases; D017239:Paclitaxel