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

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.

Decorin as a multivalent therapeutic agent against cancer

“…Mitostatin was originally identified as a decorin-inducible gene using subtractive hybridization and probes from decorin-transfected (and thereby, growth suppressed) cells [166]. Notably, mitostatin is downregulated in bladder and breast carcinomas [166,167], suggesting that it might represent a potential tumor suppressor gene. Mitostatin primarily resides at the outer mitochondrial membrane [167] and at specialized membrane:membrane contact sites at the juxtaposition of the endoplasmic reticulum and mitochondria where it interacts with mitofusion-2 [168].…”

“…Notably, mitostatin is downregulated in bladder and breast carcinomas [166,167], suggesting that it might represent a potential tumor suppressor gene. Mitostatin primarily resides at the outer mitochondrial membrane [167] and at specialized membrane:membrane contact sites at the juxtaposition of the endoplasmic reticulum and mitochondria where it interacts with mitofusion-2 [168]. Hence the given eponym for mitostatin, mitochondrial protein with oncostatic activity.…”

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

“…Mitophagic induction may, indeed, unify the classical tumoricidal functions of decorin [59]. Functioning at the core of this novel finding is a poorly studied decorin-inducible tumor suppressor known as mitostatin [133, 134]. Mitostatin, also known as trichoplein [135], localizes to mitochondria [133] as well as to highly specialized sites that exist in juxtaposition at endoplasmic reticulum-mitochondrial interfaces in conjunction with mitofusion-2 [135].…”

“…1C). Tantalizingly, selective degradation of specific mitochondrial proteins in a PINK1/Parkin dependent manner [142] occurs primarily on the outer mitochondrial membrane, where mitostatin localizes [133, 134]. …”

Decorin Induces Mitophagy in Breast Carcinoma Cells via Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) and Mitostatin

“…Upon induction, mitostatin displays several hallmarks of a classical tumor suppressor gene such as inhibiting tumor cell migration, growth, and proliferation and simultaneously triggering proapoptotic pathways (55,56). Furthermore, mitostatin is absent in ϳ35% of human prostate carcinomas (56), whereas decreased expression is associated with advanced cancer stages (55).…”