ABSTRACT: JC polyoma virus (JCPyV) is a ubiquitous polyoma virus that infects the individual to cause progressive multifocal leukoencephalopathy and malignancies. Here, we found that T-antigen knockdown suppressed proliferation, glycolysis, mitochondrial respiration, migration, and invasion, and induced apoptosis and G2 arrest. The reverse was true for T-antigen overexpression, with overexpression of Akt, survivin, retinoblastoma protein, β-catenin, β-transducin repeat-containing protein (TRCP), and inhibitor of growth (ING)1, and the underexpression of mammalian target of rapamycin (mTOR), phosphorylated (p)-mTOR, p-p38, Cyclin D1, p21, vascular endothelial growth factor (VEGF), ING2, and ING4 in hepatocellular and pancreatic cancer cells and tissues. In lens tumor cells, T antigen trans