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Epstein‐Barr virus‐encoded latent membrane protein 1 promotes stress‐induced apoptosis upstream of caspase‐2‐dependent mitochondrial perturbation
Author(s) -
Zhang Xiangning,
Uthaisang Wanlaya,
Hu LiFu,
Ernberg Ingemar T.,
Fadeel Bengt
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20553
Subject(s) - apoptosis , cytochrome c , microbiology and biotechnology , caspase , etoposide , transfection , biology , nasopharyngeal carcinoma , caspase 8 , intrinsic apoptosis , chemistry , cancer research , mitochondrion , cell culture , programmed cell death , biochemistry , medicine , genetics , radiation therapy , chemotherapy
Previous studies have shown that Epstein‐Barr virus (EBV)‐encoded latent membrane protein 1 (LMP1) enhances etoposide‐induced apoptosis in epithelial cells. Our study was undertaken to further dissect the modulation of tumor cell apoptosis by this viral protein. Using an inducible system of LMP1 expression in HeLa cells, we show herein that etoposide‐triggered apoptosis, as evidenced by nuclear condensation and caspase‐3 activation, is enhanced by LMP1. LMP1 also potentiates etoposide‐induced processing and activation of caspase‐2 in this model and enhances the dissipation of mitochondrial transmembrane potential and the release of cytochrome c in response to etoposide. Moreover, cisplatin‐triggered activation of caspases 2 and 3 is potentiated upon expression of LMP1. A similar LMP1‐mediated enhancement of cisplatin‐induced caspase activation was seen upon stable transfection of wild‐type LMP1 into the nasopharyngeal carcinoma cell line, TW03. Finally, using deletion mutants of LMP1 to determine the region of LMP1 required for apoptosis potentiation, we found that amino acids 350–386 (located within the CTAR2 domain) were responsible for sensitizing cells to cisplatin. We conclude that LMP1‐dependent potentiation of stress‐induced apoptosis occurs at an early step in the apoptosis cascade, upstream of the activation of caspase‐2, and involves the C‐terminal signaling domain of LMP1. These findings could have important ramifications for the treatment of EBV‐associated malignancies of epithelial origin, including nasopharyngeal carcinoma.