Abstract
The Bcl proteins play a critical role in apoptosis, as mutations in family members interfere with normal programmed cell death. Such events can cause cell transformation, potentially leading to cancer. Recent discoveries indicate that some viral proteins interfere with Bcl proteins either directly or indirectly; however, these data have not been systematically described. Some viruses encode proteins that reprogramme host cellular signalling pathways controlling cell differentiation, proliferation, genomic integrity, cell death, and immune system recognition. This review analyses and summarises the existing data and discusses how viral proteins interfere with normal pro- and anti-apoptotic functions of Bcl-2 and Bcl-xL. Particularly, this article focuses on how viral proteins, such as Herpesviruses, HTLV-1, HPV and HCV, block apoptosis and how accumulation of such interference predisposes cancer development. Finally, we discuss possible ways to prevent and treat cancers using a combination of traditional therapies and antiviral preparations that are effective against these viruses.
Highlights
All cancers, together, comprise the second most prevalent cause of mortality worldwide
The Bcl-2 family has emerged as a dominant regulator of apoptosis in cancer cells
The mitochondrial-mediated apoptosis pathway is regulated by anti-apoptotic and pro-apoptotic (Bad, Bcl-2-associated X protein (Bax), and Bcl-2 homologous antagonist/killer (Bak)) proteins
Summary
Together, comprise the second most prevalent cause of mortality worldwide. KSHV viral Bcl-2 (vBcl-2) is encoded by ORF16 [34] This lytic protein acts directly on the apoptotic pathways via inhibition of apoptosis induced by KSHV infection and deactivation of the pro-apoptotic protein Bax [45,46]. By inducing expression of Bcl-xL, Tax increases survival of cells infected with HTLV-1 and inhibits apoptotic signals, leading to leukaemogenesis. Inhibition of proliferation, decreased expression of Bcl-2, induction of apoptosis, and high sensitivity to chemotherapeutic agents are associated with LMP-1 suppression These observations suggest that LMP-1 suppression in EBV-associated malignancy could be a therapeutic target for cancer treatment, and Bcl-2 antisense therapy may represent a novel anti-tumour treatment strategy. The Bak gene induces apoptosis in HCC cells, despite the presence of high levels of the anti-apoptotic Bcl-2 family members [93], indicating a possible therapeutic route for controlling apoptosis in HCV-infected patients. This suggests that therapies that alter the life cycle of HCV infection, those that target NS5B RNA-dependent RNA polymerase and NS3/4A serine proteases, are potential therapeutic agents for cancer treatment [143]
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