Journal
EMBO MOLECULAR MEDICINE
Volume 2, Issue 7, Pages 275-288Publisher
WILEY
DOI: 10.1002/emmm.201000081
Keywords
EMCV; HIF; NF-kappa B; RCC; VHL
Categories
Funding
- Canadian Cancer Society [18460]
- German Research Foundation (DFG) [Ro 3750/1-1]
- Canadian Institutes of Health Research (CIHR)
- Royal Australasian College of Physicians
- National Health and Medical Research Council
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Apoptosis is a fundamental host defence mechanism against invading microbes. Inactivation of NF-kappa B attenuates encephalomyocarditis virus (EMCV) virulence by triggering rapid apoptosis of infected cells, thereby pre-emptively limiting viral replication. Recent evidence has shown that hypoxia-inducible factor (HIF) increases NF-kappa B-mediated anti-apoptotic response in clear-cell renal cell carcinoma (CCRCC) that commonly exhibit hyperactivation of HIF due to the loss of its principal negative regulator, von Hippel-Lindau (VHL) tumour suppressor protein. Here, we show that EMCV challenge induces a strong NF-kappa B-dependent gene expression profile concomitant with a lack of interferon-mediated anti-viral response in VHL-null CCRCC, and that multiple established CCRCC cell lines, as well as early-passage primary CCRCC cultured cells, are acutely susceptible to EMCV replication and virulence. Functional restoration of VHL or molecular suppression of HIF or NF-kappa B dramatically reverses CCRCC cellular susceptibility to EMCV-induced killing. Notably, intratumoural EMCV treatment of CCRCC in a murine xenograft model rapidly regresses tumour growth. These findings provide compelling pre-clinical evidence for the usage of EMCV in the treatment of CCRCC and potentially other tumours with elevated HIF/NF-kappa B-survival signature.
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