Survivin is a potential mediator of prostate cancer metastasis.
OBJECTIVE
We examined whether Survivin expression is associated with an increased risk of metastasis in prostate cancer.


METHODS
A total of 205 patients with T1 (23%) and T2 (77%) prostate cancer were treated with conventional external beam radiation therapy from 1991 to 1993 at the Massachusetts General Hospital. Of the patients, 62 had adequate and suitable-stained tumor material for Survivin analysis. Median follow-up was 102 months (range, 5-127 months). Distant failure was determined on the basis of clinical criteria. In preclinical studies, replication-deficient adenovirus encoding phosphorylation-defective Survivin Thr34→Ala dominant-negative mutant pAd-S(T34A) or short hairpin RNA (shRNA) was used to inhibit Survivin in prostate cancer models, and the cell motility, morphology, and metastasis were investigated.


RESULTS
Our correlative data on men with early-stage (T1/T2) prostate cancers treated at Massachusetts General Hospital by definitive radiotherapy indicated that overexpression of Survivin (positive staining in ≥10% cells) was associated with a significantly increased risk for the subsequent development of distant metastasis (p = 0.016) in the univariate analysis. In the multivariate analysis, overexpression of Survivin remained an independent predictor of distant metastasis (p = 0.008). The inhibition of Survivin dramatically inhibited invasiveness of prostate cancer cells in the in vitro invasion assay and spontaneous metastasis in the Dunning prostate cancer in vivo model. Furthermore, attenuation of Survivin resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility.


CONCLUSIONS
This study suggests that Survivin may be a potentially important prognostic marker and promising therapeutic target in metastatic prostate cancer.
Arthur G. James Comprehensive Cancer Center, The Ohio State University Medical School, Columbus, OH 43210, USA.
Min
M
Zhang
John J
JJ
Coen
Yoshiyuki
Y
Suzuki
Michael R
MR
Siedow
Andrzej
A
Niemierko
Li-Yan
LY
Khor
Alan
A
Pollack
Yifen
Y
Zhang
Anthony L
AL
Zietman
William U
WU
Shipley
Arnab
A
Chakravarti
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D005500:Follow-Up Studies; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D055029:Inverted Repeat Sequences; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin