Oncolytic targeting of renal cell carcinoma via encephalomyocarditis virus

Apoptosis is a fundamental host defence mechanism against invading microbes. Inactivation of NF‐κB 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‐κB‐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‐κB‐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‐κB 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‐κB‐survival signature.

[1]  J. J. de la Rosette,et al.  Biopsy of a renal mass: where are we now? , 2009, Current opinion in urology.

[2]  B. Wilson,et al.  Oxygen-independent degradation of HIF-α via bioengineered VHL tumour suppressor complex , 2009, EMBO molecular medicine.

[3]  B. Horvat,et al.  Current animal models: transgenic animal models for the study of measles pathogenesis. , 2009, Current topics in microbiology and immunology.

[4]  M. Ohh,et al.  Beyond the hypoxia-inducible factor-centric tumour suppressor model of von Hippel-Lindau , 2008, Current opinion in oncology.

[5]  B. Ebert,et al.  pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2. , 2007, Molecular cell.

[6]  M. Ohh,et al.  Mdm2-mediated NEDD8 Modification of TAp73 Regulates Its Transactivation Function* , 2006, Journal of Biological Chemistry.

[7]  G. Berx,et al.  VHL Promotes E2 Box-Dependent E-Cadherin Transcription by HIF-Mediated Regulation of SIP1 and Snail , 2006, Molecular and Cellular Biology.

[8]  M. Ohh,et al.  Loss of VHL Confers Hypoxia-Inducible Factor (HIF)-Dependent Resistance to Vesicular Stomatitis Virus: Role of HIF in Antiviral Response , 2006, Journal of Virology.

[9]  H. Atkins,et al.  A Phase 1 Clinical Study of Intravenous Administration of PV701, an Oncolytic Virus, Using Two-Step Desensitization , 2006, Clinical Cancer Research.

[10]  S. Cornelis,et al.  The polypyrimidine tract-binding protein stimulates HIF-1α IRES-mediated translation during hypoxia , 2005, Nucleic acids research.

[11]  R. Martuza,et al.  Oncolytic viral therapies – the clinical experience , 2005, Oncogene.

[12]  C. O'Shea.  Viruses: tools for tumor target discovery, and agents for oncolytic therapies – an introduction , 2005, Oncogene.

[13]  M. Rettig,et al.  Mechanism of von Hippel-Lindau Protein-Mediated Suppression of Nuclear Factor kappa B Activity , 2005, Molecular and Cellular Biology.

[14]  J. Corbett,et al.  Encephalomyocarditis Virus Induces PKR-Independent Mitogen-Activated Protein Kinase Activation in Macrophages , 2005, Journal of Virology.

[15]  K. Norman,et al.  Not all viruses are bad guys: the case for reovirus in cancer therapy. , 2005, Drug discovery today.

[16]  Daniel J Brat,et al.  Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. , 2005, Neuro-oncology.

[17]  Sankar Ghosh,et al.  Signaling to NF-kappaB. , 2004, Genes & development.

[18]  Byung Hak Kim,et al.  Inhibitory action of novel aromatic diamine compound on lipopolysaccharide‐induced nuclear translocation of NF‐κB without affecting IκB degradation , 2004 .

[19]  D. Livingston,et al.  Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. , 2004, Cancer cell.

[20]  S. Ngoi,et al.  Exploiting internal ribosome entry sites in gene therapy vector design. , 2004, Current gene therapy.

[21]  Byung Hak Kim,et al.  Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NF-kappaB without affecting IkappaB degradation. , 2004, FEBS letters.

[22]  J. Ku,et al.  Isolation and culture of renal cancer cell lines. , 2004, Methods in molecular medicine.

[23]  H. Wakimoto,et al.  Altered expression of antiviral cytokine mRNAs associated with cyclophosphamide's enhancement of viral oncolysis , 2004, Gene Therapy.

[24]  M. Ohh,et al.  The von Hippel-Lindau tumor suppressor protein sensitizes renal cell carcinoma cells to tumor necrosis factor-induced cytotoxicity by suppressing the nuclear factor-kappaB-dependent antiapoptotic pathway. , 2003, Cancer research.

[25]  H. Atkins,et al.  VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. , 2003, Cancer cell.

[26]  G. Demers,et al.  Pharmacologic indicators of antitumor efficacy for oncolytic virotherapy. , 2003, Cancer research.

[27]  R. Korneluk,et al.  Distinct Regulation of Internal Ribosome Entry Site-mediated Translation following Cellular Stress Is Mediated by Apoptotic Fragments of eIF4G Translation Initiation Factor Family Members eIF4GI and p97/DAP5/NAT1* , 2003, The Journal of Biological Chemistry.

[28]  Tak W. Mak,et al.  The role of nuclear factor-κB essential modulator (NEMO) in B cell development and survival , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Yoon Ki Kim,et al.  Continuous heat shock enhances translational initiation directed by internal ribosomal entry site. , 2002, Biochemical and biophysical research communications.

[30]  W. Kaelin,et al.  Molecular basis of the VHL hereditary cancer syndrome , 2002, Nature Reviews Cancer.

[31]  Michael Karin,et al.  NF-κB in cancer: from innocent bystander to major culprit , 2002, Nature Reviews Cancer.

[32]  Michael Karin,et al.  NF-kappaB in cancer: from innocent bystander to major culprit. , 2002, Nature reviews. Cancer.

[33]  Corrie Brown,et al.  Porcine Encephalomyocarditis Virus Persists in Pig Myocardium and Infects Human Myocardial Cells , 2001, Journal of Virology.

[34]  Hilde Bosmans,et al.  Radiofrequency Ablation for Eradication of Renal Tumor in a Rabbit Model by Using a Cooled-tip Electrode Technique , 2001, Annals of Surgical Oncology.

[35]  B. Thomson.  Viruses and apoptosis , 2001, International journal of experimental pathology.

[36]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[37]  E. Schwarz,et al.  NF-κB-Mediated Inhibition of Apoptosis Is Required for Encephalomyocarditis Virus Virulence: a Mechanism of Resistance in p50 Knockout Mice , 1998, Journal of Virology.

[38]  J. Tschopp,et al.  Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors , 1997, Nature.

[39]  P. Branton,et al.  Regulation of apoptosis by viral gene products , 1997, Journal of virology.

[40]  J. Bertin,et al.  Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Marty W. Mayo,et al.  TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-κB , 1996, Science.

[42]  David Baltimore,et al.  An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death , 1996, Science.

[43]  Seamus J. Martin,et al.  Suppression of TNF-α-Induced Apoptosis by NF-κB , 1996, Science.

[44]  P. Branton,et al.  Bcl-2 and adenovirus E1B 19 kDA protein prevent E1A-induced processing of CPP32 and cleavage of poly(ADP-ribose) polymerase. , 1996, Oncogene.

[45]  D. Baltimore,et al.  An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. , 1996, Science.

[46]  C. Y. Wang,et al.  TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. , 1996, Science.

[47]  D. Green,et al.  Suppression of TNF-alpha-induced apoptosis by NF-kappaB. , 1996, Science.

[48]  R. Moyer,et al.  A rabbitpox virus serpin gene controls host range by inhibiting apoptosis in restrictive cells , 1995, Journal of virology.

[49]  J. Mankovich,et al.  Inhibition of ICE family proteases by baculovirus antiapoptotic protein p35. , 1995, Science.

[50]  David Baltimore,et al.  Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses , 1995, Cell.

[51]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[52]  P. Hershberger,et al.  Site-specific mutagenesis of the 35-kilodalton protein gene encoded by Autographa californica nuclear polyhedrosis virus: cell line-specific effects on virus replication , 1992, Journal of virology.

[53]  R. Black,et al.  Viral inhibition of inflammation: Cowpox virus encodes an inhibitor of the interleukin-1β converting enzyme , 1992, Cell.

[54]  J. Arrand,et al.  Biological characterization of recombinant vaccinia viruses in mice infected by the respiratory route. , 1990, The Journal of general virology.

[55]  T. Shenk,et al.  Deletion of the gene encoding the adenovirus 5 early region 1b 21,000-molecular-weight polypeptide leads to degradation of viral and host cell DNA , 1984, Journal of virology.

[56]  M. Wood,et al.  Analysis and interpretation of data. , 1978, The Journal of family practice.

[57]  R. Singaravelu,et al.  Oncolytic Viruses , 2021, Nature.

[58]  M. Karno,et al.  Renal cell carcinoma. , 1956, Bulletin. Tufts-New England Medical Center.

[59]  G. H. Algire,et al.  Recent developments in the transparent-chamber technique as adapted to the mouse. , 1949, Journal of the National Cancer Institute.