{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:15:21Z","timestamp":1788369321034,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012250","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000}}],"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005847","name":"Health and Medical Research Fund","doi-asserted-by":"crossref","award":["18170462"],"award-info":[{"award-number":["18170462"]}],"id":[{"id":"10.13039\/501100005847","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005847","name":"Health and Medical Research Fund","doi-asserted-by":"crossref","award":["20190432"],"award-info":[{"award-number":["20190432"]}],"id":[{"id":"10.13039\/501100005847","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Epstein\u2013Barr virus (EBV) research grant","award":["200004525"],"award-info":[{"award-number":["200004525"]}]},{"name":"UPAM Edward & Yolanda Wong Fund"},{"name":"The University of Hong Kong Postgraduate Scholarship"},{"name":"The University of Hong Kong Postgraduate Scholarship"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Epstein-Barr virus (EBV) manipulates the ubiquitin-proteasome system and regulators of Bcl-2 family to enable the persistence of the virus and survival of the host cells through the expression of viral proteins in distinct latency patterns. We postulate that the combination of bortezomib (proteasome inhibitor) and venetoclax (Bcl-2 inhibitor) [bort\/venetoclax] will cause synergistic killing of post-transplant lymphoproliferative disorder (PTLD) through targeting the pro-survival function of latent viral proteins such as latent membrane protein-1 (LMP-1) and EBV nuclear antigen-3C (EBNA-3C). Bort\/venetoclax could synergistically kill spontaneous lymphoblastoid cell lines (sLCLs) derived from patients with PTLD and EBV-associated hemophagocytic lymphohistiocytosis by inducing DNA damage response, apoptosis and G1-S cell cycle arrest in a ROS-dependent manner. Bortezomib potently induced the expression of Noxa, a pro-apoptotic initiator and when combined with venetoclax, inhibited Mcl-1 and Bcl-2 simultaneously. Bortezomib prevented LMP-1 induced proteasomal degradation of I\u03baB\u03b1 leading to the suppression of the NF-\u03baB signaling pathway. Bortezomib also rescued Bcl-6 from EBNA-3C mediated proteasomal degradation thus maintaining the repression of cyclin D1 and Bcl-2 causing G1-S arrest and apoptosis. Concurrently, venetoclax inhibited Bcl-2 upregulated by either LMP-1 or EBNA-3C. Bort\/venetoclax decreased the expression of phosphorylated p65 and Bcl-2 at serine 70 thereby suppressing the NF-\u03baB signaling pathway and promoting apoptosis, respectively. These data corroborated the marked suppression of the growth of xenograft of sLCL in SCID mice (p&lt;0.001). Taken together, the combination of bortezomib and venetoclax targets the pro-survival function of LMP-1 and EBNA-3C of Epstein-Barr virus in spontaneous lymphoblastoid cell lines.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012250","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T17:47:53Z","timestamp":1727372873000},"page":"e1012250","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Combination of bortezomib and venetoclax targets the pro-survival function of LMP-1 and EBNA-3C of Epstein-Barr virus in spontaneous lymphoblastoid cell lines"],"prefix":"10.1371","volume":"20","author":[{"given":"Kam Pui","family":"Tam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3565-1237","authenticated-orcid":true,"given":"Jia","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3137-0886","authenticated-orcid":true,"given":"Rex Kwok Him","family":"Au-Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1089-5325","authenticated-orcid":true,"given":"Alan K. 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