Down-regulation of HIF-1alpha by oncolytic reovirus infection independently of VHL and p53.

Many oncolytic viruses are currently being tested as potential cancer therapeutic agents. To be effective, these viruses must replicate and propagate efficiently through the tumor mass. However, it is possible that the hypoxia that characterizes many tumors may be an obstacle to viral therapy because of its inhibition of viral replication and propagation. We, therefore, decided to test how oncolytic reovirus and its target cells respond to hypoxia. We found that reovirus infection suppresses hypoxia inducible factor (HIF)-1 alpha protein levels (but not transcript abundance) in colon cancer HCT116 cells under CoCl2 or hypoxia. Reovirus infection was able to reduce HIF-1 alpha levels in both von Hippel Lindau (VHL)-/- renal carcinoma A498 and p53-/- HCT116 cells, indicating that the decrease of HIF-1 alpha mediated by reovirus requires neither VHL nor p53 proteins. However, treatment with the inhibitor MG132 restored HIF-1 alpha levels, suggesting that reovirus-induced HIF-1 alpha decrease needs proteosomal activity. A498 VHL-/- cells with constitutive expression of HIF-1 alpha were relatively resistant to reovirus-induced apoptosis when compared with A498 VHL+/+ cells. However, we found that the use of YC-1 to target HIF-1 alpha promoted reovirus-induced apoptosis in A498 VHL-/- cells. Accordingly, we propose that reovirus may be used together with YC-1 as a potential therapeutic agent against chemoresistant or radioresistant tumors that are hypoxic and show increased levels of HIF-1 alpha. Cancer Gene Therapy (2010) 17, 365-372; doi:10.1038/cgt.2009.84; published online 15 January 2010