HIF-1alpha contributes to tumour-selective killing by the sigma receptor antagonist rimcazole.
We have previously reported tumour-selective killing by the sigma (sigma) receptor ligand rimcazole. We now report that rimcazole elevates hypoxia inducible factor-1alpha (HIF-1alpha) protein levels under normoxic conditions in colorectal (HCT-116) and mammary carcinoma (MDA MB 231) cells but fails to induce HIF-1alpha in normal fibroblasts or mammary epithelial cells. Combining the sigma-1 agonist (+)-pentazocine with rimcazole substantially reduces the accumulation of HIF-1alpha, confirming that the effect is mediated at least partly by antagonism of sigma-1 sites. HIF-1alpha knockdown by RNA interference attenuates rimcazole-induced cell death in both cell types. Thus, the induction of HIF-1alpha by rimcazole contributes to tumour cell killing. In a comparison of HCT-116p53+/+ and HCT-116p53-/- cells, HIF-1alpha levels are consistently higher after rimcazole treatment in HCT-116p53+/+ cells. Furthermore, although rimcazole kills HCT-116p53-/- cells, it has a more potent apoptosis-inducing effect in HCT-116p53+/+ cells. This suggests that the presence of functional p53 protein may enhance death induction by rimcazole in part through greater induction of HIF-1alpha. p53 is not required, however, for the rimcazole-induced engagement of HIF-1alpha in proapoptotic mode as HIF-1alpha knockdown attenuates rimcazole-induced death to comparable extents in p53 mutant and wild-type cell systems. Knowledge of HIF-1alpha involvement may assist the re-profiling of rimcazole and other sigma ligands as cancer therapeutics.
Achison
M
M
Surgery and Molecular Oncology, Ninewells Medical School, University of Dundee, Dundee, UK.
Boylan
M T
MT
Hupp
T R
TR
Spruce
B A
BA
D017209:Apoptosis; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D010423:Pentazocine / Q000494:pharmacology; D034622:RNA Interference; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D002227:Carbazoles; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017480:Receptors, sigma; D016159:Tumor Suppressor Protein p53; C034931:rimcazole; D010423:Pentazocine