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 journalArticle

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

Fingerprint

Esophageal Neoplasms
Cisplatin
DNA Damage
Down-Regulation
Ouabain
Mitochondrial DNA
Cell Line
Platinum
sodium-translocating ATPase
Mitochondrial Membrane Potential
DNA Fragmentation
Proteins
Aligeron
Apoptosis
Polymerase Chain Reaction
Esophageal Squamous Cell Carcinoma

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Iizuka, N., Miyamoto, K., Tangoku, A., Hayashi, H., Hazama, S., Yoshino, S., ... Oka, M. (2000). Downregulation of intracellular nm23-H1 prevents cisplatin-induced DNA damage in oesophageal cancer cells: Possible association with Na+, K+-ATPase. British Journal of Cancer, 83(9), 1209-1215.

Downregulation of intracellular nm23-H1 prevents cisplatin-induced DNA damage in oesophageal cancer cells : Possible association with Na+, K+-ATPase. / Iizuka, N.; Miyamoto, K.; Tangoku, A.; Hayashi, H.; Hazama, S.; Yoshino, S.; Yoshimura, K.; Hirose, K.; Yoshida, H.; Oka, M.

In: British Journal of Cancer, Vol. 83, No. 9, 2000, p. 1209-1215.

Research output: Contribution to journalArticle

Iizuka, N, Miyamoto, K, Tangoku, A, Hayashi, H, Hazama, S, Yoshino, S, Yoshimura, K, Hirose, K, Yoshida, H & Oka, M 2000, 'Downregulation of intracellular nm23-H1 prevents cisplatin-induced DNA damage in oesophageal cancer cells: Possible association with Na+, K+-ATPase', British Journal of Cancer, vol. 83, no. 9, pp. 1209-1215.
Iizuka, N. ; Miyamoto, K. ; Tangoku, A. ; Hayashi, H. ; Hazama, S. ; Yoshino, S. ; Yoshimura, K. ; Hirose, K. ; Yoshida, H. ; Oka, M. / Downregulation of intracellular nm23-H1 prevents cisplatin-induced DNA damage in oesophageal cancer cells : Possible association with Na+, K+-ATPase. In: British Journal of Cancer. 2000 ; Vol. 83, No. 9. pp. 1209-1215.
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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.",
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AU - Hayashi, H.

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AB - 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.

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