Viral Proteins as Emerging Cancer Therapeutics

Abstract

Viruses are obligatory intracellular parasites that originated millions of years ago. Viral elements cover almost half of the human genome sequence and have evolved as genetic blueprints in humans. They have existed as endosymbionts as they are largely dependent on host cell metabolism. Viral proteins are known to regulate different mechanisms in the host cells by hijacking cellular metabolism to benefit viral replication. Amicable viral proteins, on the other hand, from several viruses can participate in mediating growth retardation of cancer cells based on genetic abnormalities while sparing normal cells. These proteins exert discreet yet converging pathways to regulate events like cell cycle and apoptosis in human cancer cells. This property of viral proteins could be harnessed for their use in cancer therapy. In this review, we discuss viral proteins from different sources as potential anticancer therapeutics.

Keywords: anticancer drugs; apoptosis; cell cycle; proliferation; viral proteins.

Figure 1

Schematic representation of different cell death pathways mediated by viral proteins. Levels of kinases are upregulated in cancer cells due to which phosphorylation and activation of viral protein residues (NS1 and p 10.8) lead to ER stress and DNA damage response (DDR) causing mitochondrial outer membrane permeabilization (MOMP), apoptosis, and cell death. Cell cycle arrest is mediated by activation of DDR (NS1) and downstream kinases like Ataxia telangiectasia mutated (ATM) and checkpoint kinases (Chk1/2). Cell cycle progression is inhibited at the G1/S or G2/M phase of the cell cycle as respective cyclins and CDKs are inactivated upon expression of the viral proteins mediated caspase activation (Rep78). At the same time, E2F inhibition is maintained by dephosphorylation of retinoblastoma protein (pRb) by Chk1/2, finally inhibiting the transcription of proto-oncogenes. Upward arrow↑—upregulation; downward arrow↓—downregulation; circled P in blue—phosphorylation.

Figure 2

U94 regulates different mechanisms to exert its activities mainly by downregulation of proto-oncogene Src, resulting in inhibition of cancer cell proliferation both in vitro and in vivo. Secondly, U94 was found to suppress angiogenesis ex vivo by suppressing the vessel formation. The viral protein upregulates pro-apoptotic genes like Bax and Bad levels and downregulates anti-apoptotic Bcl-2 levels culminating in Caspase-9 activation. Finally, the cleavage of Poly (ADP-ribose) polymerase (PARP) results in inhibition of DNA repair and mediation of intrinsic apoptosis in cancer cells. Upward arrow↑—upregulation; downward arrow↓—downregulation.

Figure 3

Schematic representation of apoptin derived peptide (AdP) targeted signaling pathways. AdP binds to SRC- homology 3 (SH3) domain of tyrosine kinases and deactivates PI3K/Akt pathway followed by Aryl hydrocarbon nuclear translocator (ARNT) signaling and MMP-9 suppression leading to inhibition of cell migration along mediating apoptosis.

Figure 4

Schematic representation of a possible protease-mediated mechanism, triggered by ARV p17, leading to secretion of membrane-bound anti-angiogenic factors that prevent endothelial cells (EC) migration, proliferation, vessel formation, and angiogenesis. Upward arrow↑—upregulation; downward arrow↓—downregulation.

Figure 5

Alphaviral induced apoptosis facilitated by its respective non-structural protein nsp2 (encoded by replicon vector) in baby hamster kidney (BHK) fibroblasts and structural proteins E1/E2 (encoded by helper vector) in neuroblastoma and other cancer cells. E2 alone—could not mediate the same effect as E1 alone—or E1-E2 heterodimer in metastasis regulation whereas UV-inactivated SINV may commence oncolysis in the presence of E1, specifically in neuroblastoma cells. Upward arrow↑—upregulation; downward arrow↓—downregulation.