
Effect of a poly( ADP ‐ribose) polymerase‐1 inhibitor against esophageal squamous cell carcinoma cell lines
Author(s) -
Nasuno Tomomitsu,
Mimaki Sachiyo,
Okamoto Makito,
Esumi Hiroyasu,
Tsuchihara Katsuya
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12322
Subject(s) - clonogenic assay , dna repair , dna damage , cancer research , cell culture , carcinogenesis , comet assay , cell cycle , biology , poly adp ribose polymerase , parp inhibitor , microbiology and biotechnology , cell cycle checkpoint , cell , cancer , polymerase , genetics , dna
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 ( AZD 2281) on the TE ‐series ESCC cell lines. Of these eight cell lines, the clonogenic survival of one ( TE ‐6) was reduced by AZD 2281 to the level of DSB repair‐defective Capan‐1 and HCC 1937 cells. AZD 2281‐induced DNA damage was implied by increases in γ‐H2 AX 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‐H2 AX 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 RNF 8, an E3 ligase targeting γ‐H2 AX was identified. Consistent with this, polyubiquitination of γ‐H2 AX after irradiation was impaired in TE ‐6 cells. Thus, AZD 2281 induced growth retardation of the DSB repair‐impaired TE ‐6 cells. Interestingly, a strong correlation between basal expression levels of γ‐H2 AX and sensitivity to AZD 2281was 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.