title: CD95-mediated apoptosis in Burkitt's lymphoma B-cells is associated with Pim-1 down-regulation.
abstract: B-cells of the high-grade non-Hodgkin lymphoma Burkitt's lymphoma (BL) overexpress survival oncoproteins, including the proviral integration site for Moloney murine leukaemia virus kinase (Pim)-1, and become apoptosis resistant. Activated death receptor CD95 after ligation with anti-CD95 monoclonal antibody (mAb) resulted in the regression of BL via induction of apoptosis, suggesting a decrease of survival protein expression. Here, CD95-mediated apoptotic pathways in BL B-cell lines (Raji and Daudi) following treatment with anti-CD95 mAb was investigated with the cause-and-effects on pim-1 gene expression, in comparison with leukemic cell line (K562) used as CD95-negative cells. Immunohistochemical staining for CD95 and Pim-1 was performed, and the effects of anti-CD95 mAb on apoptotic signalling using western blotting, on caspase activity and cell survival of BL B-cell and leukemic cell lines were determined. We showed that Raji cells expressed more CD95 receptors than Daudi cells. Half of each population underwent apoptosis accompanied by decreased cell viability after anti-CD95 mAb treatment. Distinct extrinsic and intrinsic CD95-mediated apoptotic pathways in Raji and Daudi cells were revealed by high caspase activity and mitochondrial outer membrane permeabilization, respectively. We observed decreased Pim-1 transcript and protein expression levels with increased heat-shock protein (Hsp)70 and decreased Hsp90 expression in anti-CD95 mAb-treated cells. Throughout the study, K562 cells did not undergo apoptosis upon anti-CD95 mAb treatment. Pim-1 knockdown following to stable transfection with plasmid vectors induced apoptosis and decreased viability of BL and K562 cells. Therefore, CD95-mediated apoptosis induces Pim-1 down-regulation in BL B-cells, but Pim-1 down-regulation cannot fully eradicate BL and leukaemia.
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Sabine
authors.initials: S
authors.lastname: Matou-Nasri
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Zaki
authors.initials: Z
authors.lastname: Rabhan
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Haya
authors.initials: H
authors.lastname: Al-Baijan
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Hamad
authors.initials: H
authors.lastname: Al-Eidi
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Wesam Bin
authors.initials: WB
authors.lastname: Yahya
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Abdelkareem
authors.initials: A
authors.lastname: Al Abdulrahman
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Nasser
authors.initials: N
authors.lastname: Almobadel
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Mona
authors.initials: M
authors.lastname: Alsubeai
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors.forename: Saleh
authors.initials: S
authors.lastname: Al Ghamdi
authors.affiliation: KAIMRC, King Saud bin-Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), MNGHA, Riyadh 11426, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Alaskar
authors.affiliation: Pathology and Laboratory Medicine, KAMC, MNGHA, Riyadh 11426, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: AlBalwi
authors.affiliation: Oncology Department, KAMC, MNGHA, Riyadh, 11426, Saudi Arabia.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Alzahrani
authors.affiliation: Cell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard - Health Affairs (MNGHA), P.O. Box 22490, Riyadh 11426, Saudi Arabia. Electronic address: alabdulkarym@gmail.com.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Alabdulkareem
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; C491901:FAS protein, human; D019014:fas Receptor; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: Apoptosis; Burkitt; CD95; Daudi; Pim-1; Raji