Download Implication of mitochondrial dysfunction in tumor malignancy

Implication of mitochondrial dysfunction in tumor malignancy
Yung-Jin Kim
Department of Molecular Biology, College of Natural Sciences, Pusan National University,
Busan 609-735, Korea ([email protected])
Mitochondria play essential and various roles including production of cellular energy,
participation of numerous metabolic reactions and apoptosis. Recently, it has been reported that
mitochondrial dysfunction is associated with various pathological condition, especially cancer.
However, the underlying mechanisms for tumor malignancy induced by mitochondrial dysfunction
have not been fully understood. In this study, the effects of mitochondrial dysfunction on tumor
malignancy were initially investigated using mitochondrial-depleted ρ0 cell model. The ρ0 cells were
constructed from Hep3B hepatocarcinoma cell line and HCT116 colorectal carcinoma cell line by
treating ethidium bromide. The Hep3B/ρ0 cells showed the properties of more rapid growth, higher
invasiveness and more aggressive migration compared to their parental Hep3B. The Hep3B/ρ0 cells
had also obtained activities for angiogenesis, sorafenib-resistance and cancer stem cell (CSC).
Increased tumor growth factor-β (TGF-β) in Hep3B/ρ0 cells promoted tumor malignancy via canonical
Smad-dependent signaling pathway. Activated TGF-β signaling pathway was also induced CSC
phenotype via induction of sex determining region Y-box 2 (Sox2) expression. In addition, the
HCT116/ρ0 cells were tolerant to apoptosis induced by anti-cancer drug treatment. The anti-apoptotic
phenotype was caused by reduction of p53 via NF-κB activation in HCT116/ cells. These results
suggest that tumor malignancy might be accelerated by mitochondrial dysfunction. Taken together,
mitochondrial dysfunction plays an important role in the tumor malignancy and could be a novel
therapeutic target to cancer therapy.