title: Myxoma virus oncolytic efficiency can be enhanced through chemical or genetic disruption of the actin cytoskeleton.
abstract: Myxoma virus (MYXV) is one of many animal viruses that exhibit oncolytic properties in transformed human cells. Compared to orthopoxviruses like vaccinia (VACV), MYXV spreads inefficiently, which could compromise its use in treating tumors and their associated metastases. The VACV F11 protein promotes virus exit and rapid spread by inhibiting Rho signalling, which results in a disruption of cortical actin. We have previously shown that although MYXV lacks an F11 homolog, the F11L gene can be introduced into MYXV promoting the spread of this Leporipoxvirus in natural host cells. Here we show that the F11-encoding (F11L(+)) MYXV strain replicates to higher levels in a number of human cancer cells. We also show that F11L(+) MYXV induces better tumor control and prolonged survival of mice bearing MDA-MB-231 cancer cells. Furthermore, we show that this virus also spreads more efficiently from the site of growth in one injected tumor, to a second untreated tumor. While we focused mostly on the use of a modified MYXV we were able to show that the effects of F11 on MYXV growth in cancer cells could be mimicked through the use of pharmacological inhibition or siRNA-mediated silencing of key regulators of cortical actin (RhoA, RhoC, mDia1, or LIMK2). These data suggest that it may be possible to increase the oncolytic efficacy of wild-type MYXV using chemical inhibitors of RhoA/C or their downstream targets. Furthermore, since all viruses must overcome barriers to exit posed by structures like cortical actin, these findings suggest that the oncolytic activity of other viruses may be enhanced through similar strategies.
authors.affiliation: Department of Medical Microbiology & Immunology, University of Alberta, Edmonton Alberta, Canada.
authors.forename: Chad R
authors.initials: CR
authors.lastname: Irwin
authors.affiliation: Department of Medical Microbiology & Immunology, University of Alberta, Edmonton Alberta, Canada.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Favis
authors.affiliation: Department of Oncology, University of Alberta, Edmonton Alberta, Canada.
authors.forename: Kate C
authors.initials: KC
authors.lastname: Agopsowicz
authors.affiliation: Department of Oncology, University of Alberta, Edmonton Alberta, Canada ; Li Ka-Shing Institute of Virology, University of Alberta, Edmonton Alberta, Canada.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Hitt
authors.affiliation: Department of Medical Microbiology & Immunology, University of Alberta, Edmonton Alberta, Canada ; Li Ka-Shing Institute of Virology, University of Alberta, Edmonton Alberta, Canada.
authors.forename: David H
authors.initials: DH
authors.lastname: Evans
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry* / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002470:Cell Survival; D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D000080865:Formins; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009233:Myxoma virus / Q000502:physiology*; D050130:Oncolytic Virotherapy; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics*; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000577:Amides; C108962:DIAPH1 protein, human; D004791:Enzyme Inhibitors; C533030:F11L protein, vaccinia virus; D000080865:Formins; D011725:Pyridines; D034741:RNA, Small Interfering; D014764:Viral Proteins; C066737:RHOA protein, human; C108830:Y 27632; C102895:LIMK2 protein, human; D054461:Lim Kinases; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein