Abstract
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.
Highlights
Prostate cancer is the main cause of cancer-related death in men in most developed countries, and the most common malignancy in American males
We focused on investigating the biological function of Mitostatin in prostate cancer cells by stably transfecting PC3 and LNCaP cells with a V5-tagged Mitostatin cDNA expression construct and PC3 and DU145 cells with an anti-sense cDNA construct
DU145 Mitostatin, which is the clone with the highest expression of Mitostatin compared to parental cell expression (4.2 fold increase, cfr Figure 1B), showed the highest inhibition of colony formation (Figure 2 B)
Summary
Prostate cancer is the main cause of cancer-related death in men in most developed countries, and the most common malignancy in American males. In the United States, one over eight men will develop prostate cancer during his life and over 27,360 men are expected to die from the disease this year [1]. Molecular genetics studies of prostate cancer have identified mutations, deletions, or loss of tumor suppressor genes expression in subsets of patients with prostate cancer [2]. Loss of heterozygosity (LOH) points out the presence of suppressor genes at specific chromosomal regions in tumors. Several allelotyping studies reported the telomeric portion of chromosome 12 to be deleted in a variety of solid tumors [3,4,5,6,7,8,9,10,11], including prostate cancer [12]
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