title: Enhancement of apoptotic damage of squamous cell carcinoma cells by inhibition of the mitochondrial DNA repairing system.
abstract: Mitochondrial DNA (mtDNA) repair systems are thought to be associated with the susceptibility of cancer cells to anticancer agents. The present study investigated the relationship between the susceptibility to gamma-rays and the mtDNA repair ability of oral squamous cell carcinoma (OSC) cell lines. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and mtDNA common deletion in both nuclear and mitochondrial DNA of OSC-2, OSC-3 and OSC-6 cells (radio-sensitive cell lines) after gamma-ray-irradiation were higher than those of OSC-1, OSC-4 and OSC-5 cells (radio-resistant cell lines). Compared with OSC-2, OSC-3 and OSC-6 cells, OSC-1, OSC-4 and OSC-5 cells had higher levels of activity of phosphoinositide-3 kinase (PI-3K)/Akt and more strongly expressed 8-hydroxyguanine DNA glycosylase (OGG1), DNA polymerase gamma (POLG) and mitochondrial transcription factor A (Tfam). Down-regulation of these mtDNA-repair-associated molecules by the RNA interference technique enhanced the susceptibility of OSC-2 and OSC-5 cells to gamma-rays, and the expression of Tfam and POLG was down-regulated by inhibitors of PI-3K/Akt signaling. These results indicate that the inhibition of mtDNA repair capacity by PI-3K/Akt signal inhibitors and OGG1 down-regulator in cancer cells may be a useful strategy for cancer treatment when combined with ionizing irradiation and chemotherapeutic drugs.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kochi Medical School, Kochi University, Kochi, Japan. uetaeisaku@yahoo.co.jp
authors.forename: Eisaku
authors.initials: E
authors.lastname: Ueta
authors.forename: Eri
authors.initials: E
authors.lastname: Sasabe
authors.forename: Zhu
authors.initials: Z
authors.lastname: Yang
authors.forename: Tokio
authors.initials: T
authors.lastname: Osaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005720:Gamma Rays; D006801:Humans; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009062:Mouth Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D045647:DNA Glycosylases; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D024101:Mitochondrial Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; C413027:POLG protein, human; C479058:oxoguanine glycosylase 1, human