Infection of human cancer cells with myxoma virus requires Akt activation via interaction with a viral ankyrin-repeat host range factor.
We demonstrate that the susceptibility of human cancer cells to be infected and killed by an oncolytic poxvirus, myxoma virus (MV), is related to the basal level of endogenous phosphorylated Akt. We further demonstrate that nonpermissive tumor cells will switch from resistant to susceptible for MV infection after expression of ectopically active Akt (Myr-Akt) and that permissive cancer cells can be rendered nonpermissive by blocking Akt activation with a dominant-negative inhibitor of Akt. Finally, the activation of Akt by MV involves the formation of a complex between the viral host range ankyrin-repeat protein, M-T5, and Akt. We conclude that the Akt pathway is a key restriction determinant for permissiveness of human cancer cells by MV.
BioTherapeutics Research Group, Robarts Research Institute and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada N6G 2V4.
Gen
G
Wang
John W
JW
Barrett
Marianne
M
Stanford
Steven J
SJ
Werden
James B
JB
Johnston
Xiujuan
X
Gao
Mei
M
Sun
Jin Q
JQ
Cheng
Grant
G
McFadden
D000818:Animals; D017089:Ankyrin Repeat; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005814:Genes, Viral; D006801:Humans; D009233:Myxoma virus / Q000378:metabolism*; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; C100338:M-T5 protein, Myxoma virus; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014764:Viral Proteins; D051057:Proto-Oncogene Proteins c-akt