Effect of a poly(ADP-ribose) polymerase-1 inhibitor against esophageal squamous cell carcinoma cell lines.
Effective molecular target drugs that improve therapeutic efficacy with fewer adverse effects for esophageal cancer are highly anticipated. Poly(ADP-ribose) polymerase (PARP) inhibitors have been proposed as low-toxicity agents to treat double strand break (DSB)-repair defective tumors. Several findings imply the potential relevance of DSB repair defects in the tumorigenesis of esophageal squamous cell carcinoma (ESCC). We evaluated the effect of a PARP Inhibitor (AZD2281) on the TE-series ESCC cell lines. Of these eight cell lines, the clonogenic survival of one (TE-6) was reduced by AZD2281 to the level of DSB repair-defective Capan-1 and HCC1937 cells. AZD2281-induced DNA damage was implied by increases in γ-H2AX and cell cycle arrest at G2/M phase. The impairment of DSB repair in TE-6 cells was suggested by a sustained increase in γ-H2AX levels and the tail moment calculated from a neutral comet assay after X-ray irradiation. Because the formation of nuclear DSB repair protein foci was impaired in TE-6 cells, whole-exome sequencing of these cells was performed to explore the gene mutations that might be responsible. A novel mutation in RNF8, an E3 ligase targeting γ-H2AX was identified. Consistent with this, polyubiquitination of γ-H2AX after irradiation was impaired in TE-6 cells. Thus, AZD2281 induced growth retardation of the DSB repair-impaired TE-6 cells. Interestingly, a strong correlation between basal expression levels of γ-H2AX and sensitivity to AZD2281was observed in the TE-series cells (R(2)  = 0.5345). Because the assessment of basal DSB status could serve as a biomarker for selecting PARP inhibitor-tractable tumors, further investigation is warranted.
Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan; Department of Otorhinolaryngology, University of Kitasato Hospital, Minami-ku, Sagamihara, Kanagawa, Japan.
Tomomitsu
T
Nasuno
Sachiyo
S
Mimaki
Makito
M
Okamoto
Hiroyasu
H
Esumi
Katsuya
K
Tsuchihara
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D000077277:Esophageal Squamous Cell Carcinoma; D016195:G2 Phase / Q000187:drug effects; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D010793:Phthalazines / Q000009:adverse effects / Q000494:pharmacology*; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D044767:Ubiquitin-Protein Ligases
D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C486521:RNF8 protein, human; D044767:Ubiquitin-Protein Ligases; C531550:olaparib
DNA repair; RNF8; esophageal cancer; poly(ADP-ribose) polymerase inhibitor; γ-H2AX