Potential mechanism of resistance to TRAIL-induced apoptosis in Burkitt's lymphoma.
OBJECTIVE
Members of the tumor necrosis factor family are potent inducers of apoptosis in sensitive cells and may be suitable for novel anti-cancer therapies aimed at inducing apoptosis via the activation of receptors with the death domain on malignant cells. We characterized the sensitivity of Burkitt's lymphoma (BL) cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and anti-Fas agonist, and investigated the mechanism of resistance of BL cell lines to TRAIL and Fas apoptotic pathways.


METHODS
Epstein-Barr virus (EBV) status in BL cell lines was determined by PCR. The extent of apoptosis following exposure to TRAIL and anti-Fas agonist was measured by 7A6 antigen staining. Expression of TRAIL receptors and Fas was determined by flow cytometry and reverse transcriptase-PCR. Western blot analyses were used to determine the expression of proapoptotic and antiapoptotic proteins. NF-kappaB activity was evaluated by electrophoretic mobility shift assay.


RESULTS
The sensitivity of BL cell lines to anti-Fas agonist depended on the expression of Fas. In contrast, the expression of TRAIL receptors did not correlate with the sensitivity to TRAIL-induced apoptosis. Interestingly, EBV-infected BL cell lines which showed constitutive levels of NF-kappaB activation, were TRAIL-resistant. NF-kappaB inhibitors reversed the resistance to TRAIL-induced apoptosis.


CONCLUSIONS
Our results suggest that activation of NF-kappaB by EBV infection plays an important role in resistance of BL cell lines to TRAIL-induced apoptosis, and that NF-kappaB inhibitors may be useful adjuncts in clinical use of TRAIL against BL.
Tafuku
Senji
S
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
Matsuda
Takehiro
T
Kawakami
Hirochika
H
Tomita
Mariko
M
Yagita
Hideo
H
Mori
Naoki
N
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor