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Cisplatin sensitivity of oral squamous carcinoma cells is regulated by Na+,K+-ATPase activity rather than copper-transporting P-type ATPases, ATP7A and ATP7B

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Abstract

Purpose

Cisplatin (CDDP) is one of the major chemotherapeutic drugs, but tumor cells’ acquired resistance to CDDP limits its therapeutic potentials. One of the main reasons of resistance is reduced drug accumulation. The mechanism by which tumor cells accumulate reduced CDDP is not well elucidated yet. The aim of this study was to investigate what regulates intracellular CDDP accumulation.

Methods

Six different types of oral squamous carcinoma cells were used in this study. Assessment of CDDP sensitivity was determined by measuring the ATP level of the cells. Intracellular CDDP and copper (Cu) accumulation were measured and CDDP efflux study was conducted. Assessment of Na+,K+-ATPase α and β subunits, ATP7A and ATP7B was done by western blotting. Specific activities of Na+,K+-ATPase and copper-transporting P-type ATPase (Cu2+-ATPase) were detected and a role of Na+,K+-ATPase inhibitor in intracellular CDDP accumulation was examined.

Results

Among the cells HSC-3 and BHY cells were found most CDDP-sensitive and CDDP-resistant, respectively. The most CDDP-sensitive HSC-3 cells exhibited an increased intracellular cisplatin accumulation, high Na+,K+-ATPase activity and over-expressed Na+,K+-ATPase α and β subunits, ATP7A and ATP7B, compared to the most CDDP-resistant BHY cells, but there were no such differences between the two in the CDDP efflux level or Cu2+-ATPase activity. Moreover, pretreatment with Na+,K+-ATPase inhibitor markedly reduced intracellular cisplatin accumulation.

Conclusions

Na+,K+-ATPase activity is responsible for regulating intracellular CDDP accumulation in oral squamous carcinoma cells rather than Cu2+-ATPase.

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Authors and Affiliations

  1. Molecular Cell Pharmacology, Graduate School of Dental Medicine, Hokkaido University, Hokkaido, Japan

    Zunaid Ahmed, Yoshiaki Deyama, Yoshitaka Yoshimura & Kuniaki Suzuki

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  1. Zunaid Ahmed
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  2. Yoshiaki Deyama
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  3. Yoshitaka Yoshimura
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  4. Kuniaki Suzuki
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Correspondence to Kuniaki Suzuki.

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Ahmed, Z., Deyama, Y., Yoshimura, Y. et al. Cisplatin sensitivity of oral squamous carcinoma cells is regulated by Na+,K+-ATPase activity rather than copper-transporting P-type ATPases, ATP7A and ATP7B. Cancer Chemother Pharmacol 63, 643–650 (2009). https://doi.org/10.1007/s00280-008-0781-z

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  • DOI: https://doi.org/10.1007/s00280-008-0781-z

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