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Mitochondrial DNA (mtDNA) mutations are often observed in various cancer types. Although the correlation between mitochondrial dysfunction and cancer malignancy has been demonstrated by several studies, further research is required to elucidate the molecular mechanisms underlying accelerated tumor development and progression due to mitochondrial mutations. We generated an mtDNA-depleted cell line, ρ⁰, via long-term ethidium bromide treatment to define the molecular mechanisms of tumor malignancy induced by mitochondrial dysfunction. Mitochondrial dysfunction in ρ⁰ cells reduced drug-induced cell death and decreased the expression of pro-apoptotic proteins including p53. The p53 expression was reduced by activation of nuclear factor-κB that depended on elevated levels of free calcium in HCT116/ρ⁰ cells. Overall, these data provide a novel mechanism for tumor development and drug resistance due to mitochondrial dysfunction. [BMB Reports 2018; 51(6): 296-301].

Hepatitis B virus (HBV) encoding the HBV x protein (HBx) is a known causative agent of hepatocellular carcinoma (HCC). Its pathogenic activities in HCC include interference with several signaling pathways associated with cell proliferation and apoptosis. Mutant C-terminal-truncated HBx isoforms are frequently found in human HCC and have been shown to enhance proliferation and invasiveness leading to HCC malignancy. We investigated the molecular mechanism of the reduced doxorubicin cytotoxicity by C-terminal truncated HBx. Cells transfected with C-terminal truncated HBx exhibited reduced cytotoxicity to doxorubicin compared to those transfected with full-length HBx. The doxorubicin resistance of cells expressing C-terminal truncated HBx correlated with upregulation of the ATP binding cassette subfamily B member 1(ABCB1) transporter, resulting in the enhanced efflux of doxorubicin. Inhibiting the activity of ABCB1 and silencing ABCB1 expression by small interfering ribonucleic acid (siRNA) increased the cytotoxicity of doxorubicin. These results indicate that elevated ABCB1 expression induced by C-terminal truncation of HBx was responsible for doxorubicin resistance in HCC. Hence, co-treatment with an ABCB1 inhibitor and an anticancer agent may be effective for the treatment of patients with liver cancer containing the C-terminal truncated HBx. [BMB Reports 2019; 52(5): 330-335].

Received 10 October 2001, Accepted 13 November 2001Eukaryotic replication protein A (RPA) is a single-stranded(ss) DNA binding protein with multiple functionsin DNA replication, repair, and genetic recombination. The70-kDa subunit of eukaryotic RPA contains a conservedfour cysteine-type zinc-finger motif that has beenimplicated in the regulation of DNA replication and repair.Recently, we described a novel function for the zinc-fingermotif in the regulation of human RPA’s ssDNA bindingactivity through reduction-oxidation (redox). Here, weshow that yeast RPA’s ssDNA binding activity is regulatedby redox potential through its RPA32 and/or RPA14subunits. Yeast RPA requires a reducing agent, such asdithiothreitol (DTT), for its ssDNA binding activity. Also,under non-reducing conditions, its DNA binding activitydecreases 20 fold. In contrast, the RPA70 subunit does notrequire DTT for its DNA binding activity and is notaffected by the redox condition. These results suggest thatall three subunits are required for the regulation of RPA’sDNA binding activity through redox potential.Keywords: Replication protein A (RPA), RPA70, Single-stranded DNA binding protein, Redox