Oncolytic targeting of renal cell carcinoma via encephalomyocarditis virus.
Apoptosis is a fundamental host defence mechanism against invading microbes. Inactivation of NF-kappaB 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-kappaB-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-kappaB-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-kappaB 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-kappaB-survival signature.
Roos
Frederik C
FC
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Roberts
Andrew M
AM
Hwang
Irene I L
II
Moriyama
Eduardo H
EH
Evans
Andrew J
AJ
Sybingco
Stephanie
S
Watson
Ian R
IR
Carneiro
Leticia A M
LA
Gedye
Craig
C
Girardin
Stephen E
SE
Ailles
Laurie E
LE
Jewett
Michael A S
MA
Milosevic
Michael
M
Wilson
Brian C
BC
Bell
John C
JC
Der
Sandy D
SD
Ohh
Michael
M
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004686:Encephalomyocarditis virus / Q000235:genetics / Q000502:physiology*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1