Pharmacological manipulation of the akt signaling pathway regulates myxoma virus replication and tropism in human cancer cells.
Viruses have evolved an assortment of mechanisms for regulating the Akt signaling pathway to establish a cellular environment more favorable for viral replication. Myxoma virus (MYXV) is a rabbit-specific poxvirus that encodes many immunomodulatory factors, including an ankyrin repeat-containing host range protein termed M-T5 that functions to regulate tropism of MYXV for rabbit lymphocytes and certain human cancer cells. MYXV permissiveness in these human cancer cells is dependent upon the direct interaction between M-T5 and Akt, which has been shown to induce the kinase activity of Akt. In this study, an array of compounds that selectively manipulate Akt signaling was screened and we show that only a subset of Akt inhibitors significantly decreased the ability of MYXV to replicate in previously permissive human cancer cells. Furthermore, reduced viral replication efficiency was correlated with lower levels of phosphorylated Akt. In contrast, the PP2A-specific phosphatase inhibitor okadaic acid promoted increased Akt kinase activation and rescued MYXV replication in human cancer cells that did not previously support viral replication. Finally, phosphorylation of Akt at residue Thr308 was shown to dictate the physical interaction between Akt and M-T5, which then leads to phosphorylation of Ser473 and permits productive MYXV replication in these human cancer cells. The results of this study further characterize the mechanism by which M-T5 exploits the Akt signaling cascade and affirms this interaction as a major tropism determinant that regulates the replication efficiency of MYXV in human cancer cells.
Werden
Steven J
SJ
Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1600 SW Archer Rd., ARB Rm. R4-295, P.O. Box 100332, Gainesville, FL 32610, USA.
McFadden
Grant
G
D045744:Cell Line, Tumor; D000068876:Fingolimod Hydrochloride; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D009233:Myxoma virus / Q000502:physiology*; D009369:Neoplasms / Q000821:virology*; D019319:Okadaic Acid / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011409:Propylene Glycols / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014764:Viral Proteins / Q000502:physiology; D056189:Viral Tropism; D014779:Virus Replication
D047908:Intracellular Signaling Peptides and Proteins; C100338:M-T5 protein, Myxoma virus; D011409:Propylene Glycols; D014764:Viral Proteins; D019319:Okadaic Acid; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D020123:Sirolimus