C119
NO-sulindac inhibits the hypoxia response of prostate cancer cells via the Akt signalling pathway
Grant Stewart, Jyoti Nanda, Gordon Brown, Antony Riddick, James Ross, Fouad Habib
University of Edinburgh, Edinburgh, UK
Nitric oxide-donating non-steroidal anti-inflammatory drugs (NO-NSAIDs) are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than unnitrated NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy.
The aim of this study was to assess the effects and mechanism of action of the NO-NSAID, NO-sulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have a pro-apoptotic, cytotoxic, anti-invasion effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. However, as the oxygen concentration was reduced there was a concomitant reduction in cell death due to NO-sulindac; suggesting a degree of chemoresistance. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1α (HIF-1α) mRNA using RNAi. Nuclear levels of HIF-1α were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was phospho-Akt. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element promoter (HRE). Transfection with the myr-Akt (constitutively active Akt) plasmid reversed the NO-sulindac induced reduction in HRE activation. Real-time PCR analysis of hypoxic NO-sulindac-treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression.
Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of prostate cancer cells by inhibiting HIF-1α translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer.
