Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development

Abstract

About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers.

Keywords: Epstein–Barr virus (EBV); Kaposi’s sarcoma-associated herpesvirus (KSHV); Merkel cell polyomavirus (MCPyV); autopaghy; hepatitis B and C viruses (HBV and HCV); human T-lymphotropic virus 1 (HTLV–1); human papillomavirus (HPV); oncogenic (or carcinogenic) viruses.

FIGURE 1

A schematic illustration of the autophagic pathway. Nutrient-rich conditions stimulate mTOR kinase activation and its inhibition of the ULK1/2 complex. Low nutrients and/or growth factors stimulate AMPK, promote mTOR inhibition, and allow ULK1/2 complex to stimulate autophagy. ULK1/2 and VPS34/BECLIN 1 complexes induce autophagy and the formation of the isolation membrane. Then, autophagy-related gene (ATG)5/12 complex and LC3 promote autophagosome formation. Subsequently, autophagosomes fused with lysosomes and the contained material is finally degraded by lysosomal proteases. Essential complexes in the formation of autolysosomes are soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), Rab7, tethering factors, and VPS34/BECLIN 1 complex II (containing UVRAG) and its negative regulator Rubicon.

FIGURE 2

Oncogenic viruses and their general impact on autophagy-regulated tumorigenesis. Autophagy plays a Janus-faced role on cancer development: on one hand, it acts as a tumor suppressive mechanism by preserving genomic instability, promoting the degradation of damaged organelle and promoting the degradation of cellular oncogenes, and the removal of pathogens; on the other hand, once cancer is established, autophagy acts as an oncogenic mechanism promoting cancer progression through the reduction of cancer-related stresses, the maintenance of cancer cells stemness potential, and promoting ETM transition, metastasis, and resistance to therapy. In this context, most of the oncogenic viruses possess the capability to inhibit autophagy mainly promoting viral replication and cellular maintenance, though this favors cancer onset.

FIGURE 3

Cutaneous and mucosal oncogenic viruses and their impacts on autophagy regulation. Human papillomavirus (HPV)-mediated modulation of autophagy is mostly performed by viral oncogenes E5, E6, and E7, which act at different levels during autophagy execution. Merkel cell polyomavirus (MCPyV) negatively regulates autophagy by inhibiting VPS34/BECLIN 1 complex I and ATG7.

FIGURE 4

Hepatotropic oncogenic viruses and their impact on autophagy regulation. Hepatitis B virus (HBV) and hepatitis C virus (HCV) interfere with the autophagy pathway at different steps and depending on the stage of their disease. During infection, both viruses induce autophagosome formation and, at the same time, impair the maturation of the autophagic vesicles to favor viral replication. In particular, at the early stage of infection, HCV is able to block autophagy through Rubicon upregulation (1), while later, the virus restored autophagy completion through UVRAG induction (2). HBV and HCV induce mitophagy. In hepatocellular carcinoma (HCC) development and progression, autophagy is mostly inhibited by both viruses, but HCV mediates the activation of chaperone-mediated autophagy (CMA).

FIGURE 5

Lymphotropic oncogenic viruses and their impacts on autophagy regulation. Oncogenic herpesviruses [i.e. Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV)] infect human cells rapidly establishing latency. Autophagy is mainly inhibited during latency, thus concurring in cancer development. In contrast, autophagy is promoted in lytic reactivation, even if the autophagosome maturation is inhibited. Human T-lymphotropic virus 1 (HTLV-1) negatively regulates autophagy by stimulating the activity of the mTOR kinase and by affecting autolysosome formation.