Mitostatin Is Down-Regulated in Human Prostate Cancer and Suppresses the Invasive Phenotype of Prostate Cancer Cells

MITOSTATIN, a novel putative tumor suppressor gene induced by decorin overexpression, is expressed in most normal human tissues but is markedly down-regulated in advanced stages of mammary and bladder carcinomas. Mitostatin negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27. In this study, we demonstrated that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells not only induced a significant reduction in cell growth, but also inhibited migration and invasion. Moreover, Mitostatin inhibited colony formation in soft-agar of PC3 and LNCaP cells as well as tumorigenicity of LNCaP cells in nude mice. Conversely, targeting endogenous Mitostatin by siRNA and anti-sense strategies in PC3 and DU145 prostate cancer cells enhanced the malignant phenotype in both cell lines. In agreement of these anti-oncogenic roles, we discovered that Mitostatin was absent in ∼35% (n = 124) of prostate tumor samples and its overall reduction was associated with advanced cancer stages. Collectively, our findings indicate that MITOSTATIN may acts as a tumor suppressor gene in prostate cancer and provide a novel cellular and molecular mechanism to be further exploited and deciphered in our understanding of prostate cancer progression

MITOSTATIN, A NOVEL MITOCHONDRIAL PROTEIN, THAT ACTS AS A TUMOR SUPPRESSOR IN PROSTATE CANCER CELLS

Mitostatin is a novel putative tumor suppressor gene at chromosome 12q24.1. The 62-kD Mitostatin protein is expressed in most normal human tissues and its immunohistochemical staining is reduced in advanced stages primary breast and bladder tumors. Mitostatin expression negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27.To determine the role of Mitostatin in prostate cancer we transfected LNCaP, PC3, and DU145 prostate cancer cells with an expression vector encoding Mitostatin -V5 fusion protein or expressing the antisense cDNA of the coding sequence of Mitostatin. In addition, we silenced endogenous Mitostatin by siRNA strategies. Mitostatin expression in primary human prostate tumors was analyzed by immunohistochemistry using three tissue arrays (AccuMax Array - A222, A223 and A302) consisted of 293 0.6-mm cores.Our results demonstrate that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells in addition to induce a reduction in cell growth, significantly inhibits migration and invasion. Moreover, Mitostatin inhibits colony formation in soft-agar in PC3 and LNCaP cells and LNCaP tumorigenicity in nude mice. Conversely, targeting endogenous Mitostatin with siRNA and anti-sense strategies in PC3 and DU145 prostate cancer cells promotes transformation in both cell lines. Mitostatin immunohistochemical staining was absent in 35.5% of prostate tumor samples and its overall reduction was significantly associated with advanced stage disease.Our findings support the hypothesis that Mitostatin acts as a bona fide tumor suppressor and suggest that further investigations of Mitostatin as a useful clinical marker for diagnosis and prognosis in prostate tumors are warranted