Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death

Abstract

Cell death is a tightly regulated process which can be exploited in cancer treatment to drive the killing of the tumour. Several conventional cancer therapies including chemotherapeutic agents target pathways involved in cell death, yet they often fail due to the lack of selectivity they have for tumour cells over healthy cells. Over the past decade, research has demonstrated the existence of numerous proteins which have an intrinsic tumour-specific toxicity, several of which originate from viruses. These tumour-selective viral proteins, although from distinct backgrounds, have several similar and interesting properties. Though the mechanism(s) of action of these proteins are not fully understood, it is possible that they can manipulate several cell death modes in cancer exemplifying the intricate interplay between these pathways. This review will discuss our current knowledge on the topic and outstanding questions, as well as deliberate the potential for viral proteins to progress into the clinic as successful cancer therapeutics.

Apoptosis Triggered by ORF3 Proteins of the Circoviridae Family

“…Therefore, the study on the CAV ORF3 protein provides a unique system for identifying apoptosis pathways ( Maddika et al., 2006 ) that can kill cancer cells selectively independent of p53. Currently, many studies on the CAV ORF3 protein aim to deliver the protein as a potentially safe cancer chemotherapy drug ( Ruiz-Martínez et al., 2017 ; Castro et al., 2018 ; Wyatt et al., 2019 ). Clearly, continued studies of pathways related to cell death have obvious therapeutic value ( Hough et al., 2015 ), although the induction activities of the PCV and DuCV ORF3 proteins are weaker than the activity of the CAV ORF3 protein.…”

Viral Proteins as Emerging Cancer Therapeutics

“…The intracellular accumulation of NS1 protein owing to its bipartite nuclear localization sequence (NLS) between aa residues 194 and 216, is a major effector of the virus-induced cytotoxicity of the neoplastic cells. Furthermore, modification of specific residues (Thr-435 and Ser-473) of NS1 is important for cancer cell toxicity which is exerted, at least in part, by dysregulation of intracellular signaling pathways [ 13 ]. Cell death caused by NS1 was shown to be majorly induced by apoptosis and dependent on caspase-9-driven caspase-3 activation [ 14 ].…”

“…Small CPPs, such as Tat, are used as ideal tools for the delivery of apoptin and AdP in vitro and in vivo. Other cationic fusion systems, namely human-derived CPP 10 (hpp10), protein transduction domain 4 (PTD4), VP1 from chicken anemia virus (CVP1) were also found to penetrate tumor tissues in vivo [ 13 , 61 ]. MT23, a CPP screened by phage display in B16 melanoma cells, was shown to not able to enter normal human cells but only melanoma cells, and MT23- fused apoptin significantly inhibited tumor growth and induced cell apoptosis in B16 tumor-bearing mice.…”

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

“…As of now, the exact mechanisms by which viruses lead to tumor development are not fully understood. Several studies demonstrated that viral infection is not sufficient for cancer development by itself [11,12] but that they contribute to oncogenesis through oncogenic viral protein production, chronic inflammation, and deregulation of host cell homeostasis [2,[13][14][15][16]. Epigenetic alterations provide a common mechanism of virusinduced transformation.…”