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Differential role of FL-BID and t-BID during verotoxin-1-induced apoptosis in Burkitt's lymphoma cells.

ABSTRACT: The globotriaosylceramide Gb3 is a glycosphingolipid expressed on a subpopulation of germinal center B lymphocytes which has been recognized as the B cell differentiation antigen CD77. Among tumoral cell types, Gb3/CD77 is strongly expressed in Burkitt's lymphoma (BL) cells as well as other solid tumors including breast, testicular and ovarian carcinomas. One known ligand of Gb3/CD77 is Verotoxin-1 (VT-1), a Shiga toxin produced in specific E. coli strains. Previously, we have reported that in BL cells, VT-1 induces apoptosis via a caspase-dependent and mitochondria-dependent pathway. Yet, the respective roles of various apoptogenic factors remained to be deciphered. Here, this apoptotic pathway was found to require cleavage of the BID protein by caspase-8 as well as activation of two other apoptogenic proteins, BAK and BAX. Surprisingly however, t-BID, the truncated form of BID resulting from caspase-8 cleavage, played no role in the conformational changes of BAK and BAX. Rather, their activation occurred under the control of full length BID (FL-BID). Indeed, introducing a non-cleavable form of BID (BID-D59A) into BID-deficient BL cells restored BAK and BAX activation following VT-1 treatment. Still, t-BID was involved along with FL-BID in the BAK-dependent and BAX-dependent cytosolic release of CYT C and SMAC/DIABLO from the mitochondrial intermembrane space: FL-BID was found to control the homo-oligomerization of both BAK and BAX, likely contributing to the initial release of CYT C and SMAC/DIABLO, while t-BID was needed for their hetero-oligomerization and ensuing release amplification. Together, our results reveal a functional cooperation between BAK and BAX during VT-1-induced apoptosis and, unexpectedly, that activation of caspase-8 and production of t-BID were not mandatory for initiation of the cell death process.

SUBMITTER: Debernardi J

PROVIDER: S-EPMC5931984 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBurkitt's lymphoma is an aggressive B-cell lymphoma that occurs in children and adults and is largely curable with the use of intensive and toxic chemotherapy. Current treatments are less effective and have more severe side effects in adults and patients with immunodeficiency than in children.MethodsWe studied low-intensity treatment consisting of infused etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) in patients with untreated Burkitt's lymphoma. Two EPOCH-R regimens were tested: a standard dose-adjusted combination in human immunodeficiency virus (HIV)-negative patients (DA-EPOCH-R group) and a lower-dose short-course combination with a double dose of rituximab in HIV-positive patients (SC-EPOCH-RR group).ResultsA total of 30 consecutive patients were treated; 19 patients were in the DA-EPOCH-R group, and 11 in the SC-EPOCH-RR group. The overall median age of the patients was 33 years, and 40% were 40 years of age or older; 73% of the patients had intermediate-risk disease, and 10% had high-risk disease. The principal toxic events, fever and neutropenia, were observed during 22% of the DA-EPOCH-R treatment cycles and 10% of the SC-EPOCH-RR treatment cycles. The tumor lysis syndrome developed in 1 patient; no treatment-related deaths occurred. The median cumulative doses of doxorubicin-etoposide and cyclophosphamide administered in the SC-EPOCH-RR group were 47% and 57% lower, respectively, than those administered in the DA-EPOCH-R group. With median follow-up times of 86 months in the DA-EPOCH-R group and 73 months in the SC-EPOCH-RR group, the rates of freedom from progression of disease and overall survival were, respectively, 95% and 100% with DA-EPOCH-R and 100% and 90% with SC-EPOCH-RR. None of the patients died from Burkitt's lymphoma.ConclusionsIn this uncontrolled prospective study, low-intensity EPOCH-R-based treatment was highly effective in adults with sporadic or immunodeficiency-associated Burkitt's lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov numbers, NCT00001337 and NCT00006436.).

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Differential role of FL-BID and t-BID during verotoxin-1-induced apoptosis in Burkitt's lymphoma cells.

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