Mitochondrial DNA (mtDNA) mutations are frequently found in a variety of tumors. However, the role of mtDNA mutations in tumor behavior is poorly understood. We explored the effects of mtDNA mutations on tumor phenotype employing mtDNA-depleted SK-Hep1 rho0 hepatoma cells. Expression of hypoxia inducible factor (HIF)-2alpha mRNA was markedly increased in rho0 cells compared to control cells. Protein level of HIF-2alpha was increased in SK-Hep1 rho0 cells compared to control cells in hypoxic but not in normoxic conditions, suggesting that mitochondrial dysfunction increases angiogenic potential of tumor cells. Expression of HIF-2alpha was increased at the RNA level after treatment of SK-Hep1 hepatoma cells with ethidium bromide (EtBr) or inhibitors of mitochondrial complexes. HIF reporter activity and the expression of vascular endothelial growth factor (VEGF), an angiogenic key molecule induced by HIF, were increased in SK-Hep1 rho0 cells compared to their normal counterparts. Tube formation assay and chick chorioallantoic membrane (CAM) assay showed that conditioned medium (CM) from mtDNA-depleted SK-Hep1 rho0 cells increased formation of tube-like structures and new blood vessels relative to that from control cells. In SK-Hep1 rho0 cells, expression of genes related to invasion such as urokinase-type plasminogen activator (uPA) or matrix metalloproteases (MMPs) was also upregulated compared to control cells, suggesting that mitochondrial dysfunction could also increase invasive potential of tumor cells. These results strongly suggest that HIF-2alpha mRNA expression is increased in tumor cells with mtDNA mutations or deletions, which contributes to the angiogenic and invasive potential of tumor cells.
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Cell Death Discov
October 2022
Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio Science and Division of Endocrinology, Department of Internal Medicine, Soonchunhyang Medical Center, Soonchunhyang University College of Medicine, Cheonan, Korea.
In ferroptosis, the roles of mitochondria have been controversial. To explore the role of mitochondrial events in ferroptosis, we employed mitochondrial DNA-depleted ρ cells that are resistant to cell death due to enhanced expression of antioxidant enzymes. Expression of mitochondrial-type GPx4 (mGPx4) but no other forms of GPx4 was increased in SK-Hep1 ρ cells.
View Article and Find Full Text PDFInt J Oncol
January 2012
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
Mitochondrial DNA-depleted ρ0 cells are resistant to apoptosis, but the mechanism remains unclear. A human hepatoma cell line (SK-Hep1) depleted of mtDNA (ρ0SK-Hep1) was induced by ethidium bromide treatment. The ρ0SK-Hep1 cells were resistant to both doxorubicin- and cisplatin-induced apoptosis, while cybrids (SK-Hep1Cyb) prepared by fusing ρ0SK-Hep1 cells with platelets showed restored susceptibility to both drugs.
View Article and Find Full Text PDFOncol Rep
March 2010
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Mitochondrial DNA (mtDNA) mutations are frequently found in a variety of tumors. However, the role of mtDNA mutations in tumor behavior is poorly understood. We explored the effects of mtDNA mutations on tumor phenotype employing mtDNA-depleted SK-Hep1 rho0 hepatoma cells.
View Article and Find Full Text PDFBiochem Biophys Res Commun
December 2004
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Republic of Korea.
We have reported that mitochondrial DNA-depleted rho(0) cells are resistant to cell death. Because aged cells have frequent mitochondrial DNA mutations, the resistance of rho(0) cells against cell death might be related to the apoptosis resistance of aged cells and frequent development of cancers in aged individuals. We studied if rho(0) cells have features simulating aged cells.
View Article and Find Full Text PDFAnn N Y Acad Sci
April 2004
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea.
Mitochondrion is one of the master players in both apoptosis and necrosis. However, most previous articles report that mitochondrial DNA-depleted cells without oxidative phosphorylation underwent apoptosis by several apoptotic effectors as efficiently as their parental cells, suggesting that intact mitochondrial function is dispensable for the progression of apoptosis. We studied the role of mitochondrial function in several apoptosis models.
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