Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors
Abstract
:1. Introduction
2. The Ubiquitin-Proteasome System
2.1. Structure and Function of Proteasome
2.2. Proteasomal Degradation Mediated by Ubiquitination
3. Interaction of EBV with Ubiquitin-Proteasome System in Host Cells
3.1. Immunological Evasion
3.2. Modulation of Cell Cycle Checkpoints
3.3. Inhibition of Apoptosis
4. Rationale of Using Proteasome Inhibitor to Treat EBV-Associated Cancers
4.1. Overview of Proteasome Inhibitors
4.2. Effect of Proteasome Inhibitors on Cell Cycle of EBV-Associated Malignancies
4.3. Effect of Proteasome Inhibitors on Apoptosis of EBV-Associated Malignancies
4.4. Reactivation of Viral Lytic Cycle by Proteasome Inhibitors
4.5. Effect of Proteasome Inhibitors on Immune Evasion
5. Potential Novel Viral-Targeted Strategies against EBV-Associated Cancers by Combination of Proteasome and Histone Deacetylase (HDAC) Inhibitors
5.1. Combination of Proteasome and HDAC Inhibitors on EBV-Associated Epithelial Malignancies
5.2. Combination of Proteasome and HDAC Inhibitors on EBV-Associated Lymphoid Cells
5.3. Pre-Clinical Data of Combination of Proteasome and HDAC Inhibitors on Treatment of EBV-Associated Malignancies
6. Concluding Remarks
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Viruses | Oncogenic Proteins/Molecules Involved | Proteins Processed by UPS | Mechanisms | Cell Function Affected | References |
---|---|---|---|---|---|
EBV | BDLF3 | MHC I & II | Postulated E3 ligase for degradation of MHC molecules is not identified yet | Immune evasion | [18] |
EBNA-1 | EBNA-1 | Inhibits proteasomal processing of EBNA-1 antigenic peptides | Immune evasion | [16] | |
p53 | Interacts with USP7, leading to ubiquitination and proteasomal degradation | Apoptosis inhibition | [33] | ||
EBNA-3C | pRb | Stabilizes cyclin D1/CDK6 and recruits SCFSkp2 E3-ubiquitin ligase to facilitate the proteasomal degradation of pRb | Cell cycle deregulation (Bypass sub-G1 arrest) | [22,23] | |
p21WAF1 | Physically interacts with Pim-1 which in turn phosphorylates p21 and enhances poly-ubiquitination of p21 for degradation | Cell cycle deregulation (Bypass G1 arrest) Apoptosis inhibition | [24] | ||
p27KIP1 | Enhances the phosphorylation and proteasomal degradation of p27KIP1 through SCFSkp2 E3-ubiquitin ligase | Cell cycle deregulation (Bypass G1 & G2/M arrest) | [25] | ||
Bcl-6 | Interacts with Bcl-6 and promotes its ubiquitination and proteasomal degradation | Cell cycle deregulation (Bypass G1 arrest) Apoptosis inhibition (release of Bcl-2) | [26] | ||
p53 | Recruits and stabilizes MDM2 E3 ligase for proteasomal degradation of p53 | Apoptosis inhibition | [34,66,67] | ||
LMP-1 | p100 | Induces proteolysis of p100 to p52 through proteasome and activates non-canonical NF-κB pathway | Apoptosis inhibition | [32] | |
KSHV | K/V cyclin | p27KIP1 | Interacts with CDK6 and phosphorylates p27KIP1 for proteasomal degradation | Cell cycle deregulation (Bypass G1 & G2/M arrest) | [29,30] |
LANA (CR1 repeat) | N/A | Inhibits proteasomal processing of LANA antigenic peptides | Immune evasion | [17] | |
RTA | IRF3 & IRF7 | Promotes proteasomal degradation of IRF3 & IRF7 directly or through stabilization of RAUL | Immune evasion | [21] | |
vIRF4 | p53 | Inhibits phosphorylation of p53 by ATM and interacts with MDM2 to facilitate proteasomal degradation of p53 | Apoptosis inhibition | [35,36] |
Proteasome Inhibitor | Type | Viral Protein Affected | Lytic Reactivation | Clinical Development | Structure |
---|---|---|---|---|---|
Bortezomib | Boronate | EBNA-3C (combination with SAHA or romidepsin) | EBV KSHV HSV-1 | FDA-approved for MM, MCL and RRMM [39] | |
Carfilzomib | Epoxyketone | N.D. | EBV | FDA-approved for RRMM [117] | |
Ixazomib | Boronate | N.D. | N.D. | FDA-approved for RRMM Phase I clinical trials in AML, follicular lymphoma and peripheral T-cell lymphoma [118] | |
Marizomib | β-lactone | N.D. | N.D. | Phase I clinical trials in RRMM, solid tumors and lymphoma | |
CEP-18770 | Boronate | N.D. | N.D. | Phase I–II clinical trials in RRMM | |
ONX-0912 | Epoxyketone | N.D. | N.D. | Phase I clinical trials in haematological solid malignancies |
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Hui, K.F.; Tam, K.P.; Chiang, A.K.S. Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors. Viruses 2017, 9, 352. https://doi.org/10.3390/v9110352
Hui KF, Tam KP, Chiang AKS. Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors. Viruses. 2017; 9(11):352. https://doi.org/10.3390/v9110352
Chicago/Turabian StyleHui, Kwai Fung, Kam Pui Tam, and Alan Kwok Shing Chiang. 2017. "Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors" Viruses 9, no. 11: 352. https://doi.org/10.3390/v9110352