Downregulation of intracellular nm23-H1 prevents cisplatin-induced DNA damage in oesophageal cancer cells: Possible association with Na+, K+-ATPase

N. Iizuka, K. Miyamoto, A. Tangoku, H. Hayashi, S. Hazama, S. Yoshino, K. Yoshimura, K. Hirose, H. Yoshida, M. Oka

Research output: Contribution to journalArticlepeer-review

Abstract

Previously, we showed that expression of nm23-H1 is associated inversely with sensitivity to cisplatin in human oesophageal squamous cell carcinoma (OSCC). The present study was undertaken to investigate the association of nm23-H1 expression with cisplatin-induced DNA damage in OSCC using antisense nm23-H1 transfectants. YES-2/AS-12, an antisense nm23-H1-transfected OSCC cell line, showed significantly reduced expression of intracellular nm23-H1 protein compared with that in parental YES-2 cells and YES-2/Neo transfectants. Surface expression of nm23-H1 protein was not observed in any of the three cell lines. PCR analysis for DNA damage demonstrated that YES-2/AS-12 cells were more resistant to nuclear and mitochondrial DNA damage by cisplatin than were YES-2/Neo cells. In addition, mitochondrial membrane potentials and DNA fragmentation assays confirmed that YES-2/AS-12 was more resistant than YES-2/Neo to apoptosis induced by cisplatin. In contrast, YES-2/AS-12 was more sensitive to ouabain, a selective inhibitor of Na+, K+-ATPase, than YES-2 and YES-2/Neo. Pre-treatment with ouabain resulted in no differences in cisplatin sensitivity between the three cell lines examined. Intracellular platinum level in YES-2/AS-12 was significantly lower than that in YES-2 and YES-2/Neo following incubation with cisplatin, whereas ouabain pre-treatment resulted in no differences in intracellular platinum accumulations between the three cell lines. Our data support the conclusion that reduced expression of intracellular nm23-H1 in OSCC cells is associated with cisplatin resistance via the prevention of both nuclear and mitochondrial DNA damage and suggest that it may be related to Na+, K+-ATPase activity, which is responsible for intracellular cisplatin accumulation. (C) 2000 Cancer Research Campaign.

Original languageEnglish (US)
Pages (from-to)1209-1215
Number of pages7
JournalBritish Journal of Cancer
Volume83
Issue number9
StatePublished - 2000
Externally publishedYes

Keywords

  • Cisplatin
  • DNA damage
  • Mitochondrial membrane potential
  • nm23
  • Oesophageal squamous cell carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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