HIF-1α contributes to tumour-selective killing by the sigma receptor antagonist rimcazole

M. Achison, M. T. Boylan, T. R. Hupp, B. A. Spruce

    Research output: Contribution to journalArticle

    17 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)1137-1146
    Number of pages10
    JournalOncogene
    Volume26
    Issue number8
    DOIs
    Publication statusPublished - 22 Feb 2007

    Keywords

    • Apoptosis
    • Carbazoles
    • Cell Line, Tumor
    • Epithelial Cells
    • Fibroblasts
    • Humans
    • Hypoxia-Inducible Factor 1, alpha Subunit
    • Neoplasms
    • Pentazocine
    • RNA Interference
    • Receptors, sigma
    • Tumor Suppressor Protein p53
    • Up-Regulation

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