Heme oxygenase-1 accelerates protumoral effects of nitric oxide in cancer cells.
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 microM) 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 microM nitrite. The recovery of DXR-induced growth inhibition was closely associated with an increase in Bcl-2 in the presence of <10 microM nitrite. Vascular endothelial growth factor (VEGF) secretion was also increased in the presence of <10 and <20 microM 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.
Sasaki
Takamitsu
T
Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 734-8521, Japan.
Yoshida
Kazuhiro
K
Kondo
Hideaki
H
Ohmori
Hitoshi
H
Kuniyasu
Hiroki
H
D002292:Carcinoma, Renal Cell; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000502:physiology*; D051547:Heme Oxygenase-1; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D008565:Membrane Proteins; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000008:administration & dosage; D009599:Nitroprusside / Q000008:administration & dosage; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011471:Prostatic Neoplasms; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D001749:Urinary Bladder Neoplasms; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; D009599:Nitroprusside; D009569:Nitric Oxide; D004317:Doxorubicin; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1