Survivin Is a Potential Mediator of Prostate Cancer Metastasis

Purpose

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

Methods and Materials

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.

Introduction

Metastatic prostate cancer is one of the leading causes of cancer death in men. An estimated 186,320 new cases will occur in the US during 2008, and 28,660 men are expected to die from the disease (1). Although there have been significant advances in the early detection and treatment of localized prostate cancer, invasion and metastasis, the key determinant of lethality in the disease, still represents a major clinical challenge. Therefore, identification of the molecular mechanisms that lead to distant metastasis is critical for improvement of the treatments for metastatic prostate cancer and for development of strategies to prevent primary prostate cancer from metastasizing 2, 3, 4.

Survivin, the smallest member of the inhibitor of apoptosis (IAP) family, is a 142-amino acid, 16.5-kDa protein coded by a single-copy gene on the human 17q25 chromosome. The two main reasons for considering Survivin as an attractive therapeutic target in cancer are its differential expression in tumors vs. normal tissues and its potential requirement for maintaining cancer-cell viability 5, 6. Survivin has not been found to be expressed in normal secretory epithelium of the prostate but has been found to be strongly expressed in prostate cancer cells (7). Furthermore, Survivin has been found to be expressed in biologically aggressive prostate cancers with higher Gleason scores and metastasis to the regional lymph node 8, 9. We have found that IGFR1-mediated upregulation of Survivin via PI3K signaling may represent an important mechanism of regulation of its expression in prostate cancer cells and resistance to antiandrogen therapy. Antagonism of Survivin appears to greatly enhance the sensitivity of prostate cancer cells to antiandrogen therapy and chemotherapy 10, 11. In this present study, we investigate the role of Survivin in mediating prostate cancer metastasis.