title: Latent membrane protein 1 of Epstein-Barr virus sensitizes cancer cells to cisplatin by enhancing NF-κB p50 homodimer formation and downregulating NAPA expression.
abstract: Expression of the oncogenic latent membrane protein 1 (LMP1) of Epstein-Barr virus is involved in the pathogenesis of nasopharyngeal carcinoma (NPC) and lymphoma. In previous studies, we found that expression of LMP1 was sufficient to transform BALB/c-3T3 cells. In contrast, other studies have shown that LMP1 induces apoptosis in a NF-κB-dependent manner and also inhibits the growth of tumors in mice, thereby indicating that LMP1 may produce various biological effects depending on the biological and cellular context. Still, the mechanism underlying the pro-apoptotic activity of LMP1 remains unclear. In the present study, we found that LMP1 inhibits the expression of NAPA, an endoplasmic reticulum SNARE protein that possesses anti-apoptotic properties against the DNA-damaging drug cisplatin. Accordingly, LMP1-transformed BALB/c-3T3 cells were sensitized to cisplatin-induced apoptosis, whereas no sensitization effect was noted following treatment with the mitotic spindle-damaging drugs vincristine and taxol. Knockdown of LMP1 with antisense oligonucleotides restored NAPA protein level and rendered the cells resistant to cisplatin. Similarly, overexpression of NAPA reduced the effect of LMP1 and induced resistance to cisplatin. LMP1 was shown to upregulate the NF-κB subunit p50, leading to formation of p50 homodimers on the NAPA promoter. These findings suggest that the viral protein LMP1 may sensitize cancer cells to cisplatin chemotherapy by downregulating NAPA and by enhancing the formation of p50 homodimers which in turn inhibit the expression of NF-κB regulated anti-apoptotic genes. These findings provide an explanatory mechanism for the pro-apoptotic activity of LMP1 as well as new therapeutic targets to control tumor growth.
authors.affiliation: Department of Biochemistry and Molecular Biology, Chang Gung University, Taoyuan 333, Taiwan, ROC. d9601101@stmail.cgu.edu.tw
authors.forename: Zchong-Zcho
authors.initials: ZZ
authors.lastname: Wu
authors.forename: Kai-Ping N
authors.initials: KP
authors.lastname: Chow
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Kuo
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
authors.forename: Chuck C-K
authors.initials: CC
authors.lastname: Chao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D041702:BALB 3T3 Cells; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D020868:Gene Silencing; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D050791:STAT Transcription Factors; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D014763:Viral Matrix Proteins; D053613:Janus Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D002945:Cisplatin