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Heme oxygenase-1 accelerates protumoral effects of nitric oxide in cancer cells

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Abstract

We examined the biological effects of nitric oxide (NO) and its mediator, heme oxygenase-1 (HO-1), in cancer. Urogenital cancer cell lines, SKRC, T24 and DU145, were treated with various concentrations of sodium nitroprusside (SNP), a NO donor. The medium nitrite concentration was exponentially increased according to the concentration of SNP. Cell growth inhibition by NO was observed only at high nitrite concentrations (>20 μM) in DU145 and T24 cells. Nitrite did not inhibit the growth of SKRC cells at any of the concentrations used. Doxorubicin (DXR) inhibited cell growth in the three cell lines, whereas growth inhibition recovered in the presence of <10 μM nitrite. The recovery of DXR-induced growth inhibition was closely associated with an increase in Bcl-2 in the presence of <10 μM nitrite. Vascular endothelial growth factor (VEGF) secretion was also increased in the presence of <10 and <20 μM nitrite, respectively, in DU145 and SKRC or T24 cells. The expression of HO-1 was associated with sensitivity to NO-induced growth inhibition at constitutive levels, and was induced by SNP treatment. HO-1 inhibition by HO-1 antisense S-oligodeoxynucleotide treatment increased NO-induced growth inhibition, and decreased Bcl-2 expression or VEGF secretion in the three cell lines. These findings suggest that the NO/HO-1 system has protumoral effects.

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Abbreviations

DXR:

Doxorubicin

ELISA:

Enzyme-linked immunosorbent assay

HO:

Heme oxygenase

NO:

Nitric oxide

S-ODN:

18-Mer S-oligodeoxynucleotide

SNP:

Sodium nitroprusside

TAMs:

Tumor-associated macrophages

VEGF:

Vascular endothelial growth factor

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Acknowledgements

We thank Miss Kaori Obara for excellent assistance in preparing the manuscript.

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Authors and Affiliations

  1. Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 734-8521, Japan

    Takamitsu Sasaki, Hideaki Kondo, Hitoshi Ohmori & Hiroki Kuniyasu

  2. Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Kazuhiro Yoshida

Authors
  1. Takamitsu Sasaki
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  2. Kazuhiro Yoshida
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  3. Hideaki Kondo
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  4. Hitoshi Ohmori
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  5. Hiroki Kuniyasu
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Corresponding author

Correspondence to Hiroki Kuniyasu.

Additional information

This work was supported by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (KAKENHI: 15390130).

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Sasaki, T., Yoshida, K., Kondo, H. et al. Heme oxygenase-1 accelerates protumoral effects of nitric oxide in cancer cells. Virchows Arch 446, 525–531 (2005). https://doi.org/10.1007/s00428-005-1247-x

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  • DOI: https://doi.org/10.1007/s00428-005-1247-x

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