A Metabolomics Investigation of the Metabolic Changes of Raji B Lymphoma Cells Undergoing Apoptosis Induced by Zinc Ions

Zinc plays a pivotal role in the function of cells and can induce apoptosis in various cancer cells, including Raji B lymphoma. However, the metabolic mechanism of Zn-induced apoptosis in Raji cells has not been explored. In this study, we performed global metabolic profiling using UPLC−Orbitrap−MS to assess the apoptosis of Raji cells induced by Zn ions released from ZnO nanorods. Multivariate analysis and database searches identified altered metabolites. Furthermore, the differences in the phosphorylation of 1380 proteins were also evaluated by Full Moon kinase array to discover the protein associated Zn−induced apoptosis. From the results, a prominent increase in glycerophosphocholine and fatty acids was observed after Zn ion treatment, but only arachidonic acid was shown to induce apoptosis. The kinase array revealed that the phosphorylation of p53, GTPase activation protein, CaMK2a, PPAR−γ, and PLA−2 was changed. From the pathway analysis, metabolic changes showed earlier onset than protein signaling, which were related to choline metabolism. LC−MS analysis was used to quantify the intracellular choline concentration, which decreased after Zn treatment, which may be related to the choline consumption required to produce choline-containing metabolites. Overall, we found that choline metabolism plays an important role in Zn-induced Raji cell apoptosis.

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The role of bcl-xL in CD40-mediated rescue from anti-μ-induced apoptosis in WEHI-231 B lymphoma cells

European Journal of Immunology ◽

10.1002/eji.1830250533 ◽

1995 ◽

Vol 25 (5) ◽

pp. 1352-1357 ◽

Cited By ~ 113

Author(s):

Michael S. K. Choi ◽

Lawrence H. Boise ◽

Alexander R. Gottschalk ◽

José Quintans ◽

Craig B. Thompson ◽

...

Keyword(s):

Lymphoma Cells ◽

B Lymphoma ◽

B Lymphoma Cells ◽

Wehi 231 ◽

Induced Apoptosis

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Phospho-SFKs (Y416) As a Potential Predictive Marker for Dasatinib Therapy in B-Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia,

Blood ◽

10.1182/blood.v118.21.3727.3727 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3727-3727

Author(s):

Xiaoxian Zhao ◽

Eric D. Hsi

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Predictive Marker ◽

Lymphocytic Leukemia ◽

Lymphoma Cell ◽

Raji Cells ◽

B Lymphoma ◽

Induced Apoptosis

Abstract Abstract 3727 The Src family of protein tyrosine kinases (SFKs) plays an important role in regulating multiple signaling networks including B-cell receptors (BCR) mediated pathways and abnormal SFK kinase activation promotes B lymphoma cell survival. Dasatinib is an oral BCR/ABL1 and SKF inhibitor useful in the treatment of imatinib-resistant CML and Ph+ALL. Given its broad inhibitory activity, dasatinib may be useful in the treatment of other hematologic malignancies and having a biologic predictor of response would be helpful in rational selection of this targeted therapeutic. We hypothesized this agent could have therapeutic potential against lymphoma patients with p-SFK (Y416) expression. Constitutive p-SFK (Y416) expression (indicating active SFK signaling) was detected in both B-lymphoma cell lines and a subset of primary lymphoma tissues including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Burkitt lymphoma and small lymphocytic leukemia (SLL). Dasatinib induced apoptosis of B-lymphoma Raji cells correlated with high level expression of constitutive p-SFK (Y416) and dasatinib rapidly reduced the global level of tyrosine phosphorylations including p-SFK (Y416) in Raji cells. 19 of 28 lymphoma cases (67.9%) were positive for p-SFK (Y416) by Western blot analysis. Dasatinib displayed in vitro dose-dependent (10–200 nM) killing activity against 17 of those 19 p-SFK (Y416) cases (89.5%). In contrast, only 2 of 9 p-SFK (Y416) negative cases (22.2%) had response to dasatinib exposure. Thus presence of p-SFK (Y416) was associated with in vitro response to dasatinib (p <0.0001). Similar to tested Raji cells, dasatinib induced apoptosis of primary B-cell lymphoma cells was accompanied with de-phosphorylation of p-SFK (Y416) and cleavage of caspase-3. 6 of 9 tested CLL cases were p-SFK (Y416) positive. Dasatinib displayed in vitro killing activities against 5 of 6 positive cases with a range of killing from 12% to 53% (mean 26.5%) of malignant B-cells. Meanwhile, one of three negative cases showed response to dasatinib (17% killing). We conclude that p-SFK (Y416) may be a useful predictive marker of response to dasatinib. Potential uses include pharmacodynamic monitoring or integral biomarker for selecting appropriate patients with B-cell malignancies for clinical trials. Disclosures: No relevant conflicts of interest to declare.

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A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis

eLife ◽

10.7554/elife.00822 ◽

2013 ◽

Vol 2 ◽

Cited By ~ 57

Author(s):

Virginie Olive ◽

Erich Sabio ◽

Margaux J Bennett ◽

Caitlin S De Jong ◽

Anne Biton ◽

...

Keyword(s):

Mature Mirnas ◽

New Paradigm ◽

Functional Interaction ◽

B Lymphoma ◽

B Lymphoma Cells ◽

Complex Modes ◽

Proliferation And Apoptosis ◽

Proteosomal Degradation ◽

Induced Apoptosis ◽

Excessive Proliferation

mir-17-92, a potent polycistronic oncomir, encodes six mature miRNAs with complex modes of interactions. In the Eμ-myc Burkitt’s lymphoma model, mir-17-92 exhibits potent oncogenic activity by repressing c-Myc-induced apoptosis, primarily through its miR-19 components. Surprisingly, mir-17-92 also encodes the miR-92 component that negatively regulates its oncogenic cooperation with c-Myc. This miR-92 effect is, at least in part, mediated by its direct repression of Fbw7, which promotes the proteosomal degradation of c-Myc. Thus, overexpressing miR-92 leads to aberrant c-Myc increase, imposing a strong coupling between excessive proliferation and p53-dependent apoptosis. Interestingly, miR-92 antagonizes the oncogenic miR-19 miRNAs; and such functional interaction coordinates proliferation and apoptosis during c-Myc-induced oncogenesis. This miR-19:miR-92 antagonism is disrupted in B-lymphoma cells that favor a greater increase of miR-19 over miR-92. Altogether, we suggest a new paradigm whereby the unique gene structure of a polycistronic oncomir confers an intricate balance between oncogene and tumor suppressor crosstalk.

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Complement Enhances Foxp3+ T Regulatory Cell Induction by B Cell Lymphoma

Blood ◽

10.1182/blood.v116.21.5176.5176 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5176-5176

Author(s):

Suresh Veeramani ◽

Chris Dahle ◽

George Weiner

Keyword(s):

T Cells ◽

Human Serum ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Treg Cells ◽

Lymphoma Cells ◽

Complement Components ◽

Raji Cells ◽

B Lymphoma ◽

B Lymphoma Cells

Abstract Abstract 5176 The effect of complement on the immune system is complex and includes inhibition of aspects of the immune response. For example, we previously reported that C3b can inhibit the ability of mAb to activate NK cell-mediated antibody-dependent cellular cytotoxicity and that polymorphisms in C1q associated with lower C1q levels correlate with better therapeutic outcome. Polymorphisms in C5 and C9 complement components have also been shown to be associated with lymphoma risk. The current studies were designed to assess whether complement components may exert their inhibitory effects through the immune regulatory network, such as that mediated by T regulatory (Treg) cells. Peripheral Blood Mononuclear Cells (PBMCs) from healthy donors were co-cultured with Raji B cell lymphoma cells for 48 hours in the presence of unmodified autologous human serum or complement-depleted serum [heat-inactivated (HI) or cobra-venom factor (CVF)-treated serum]. Cells were stained with anti-CD3-APC-Cy7, CD4-PE-Cy7, CD25-PerCP-Cy5.5 and Foxp3-APC and the percent of CD4+ T-cells that were CD25highFoxp3+ (henceforth referred to as Tregs) determined. The ability of cells cultured in this manner to inhibit granzyme B expression in PHA-activated CD8+ autologous T cells was also determined. Tregs were not induced when PBMCs were cultured without Raji cells regardless of whether the cells were cultured in serum (data not shown). However, PBMCs co-cultured with Raji B lymphoma cells showed significantly higher percentages of Tregs in the presence of unmodified human serum (*p=0.0387) when compared to HI or CVF-treated human serum (**p=0.0370 and 0.0227, respectively) (Fig. 1). Tregs enriched from PBMCs cultured with unmodified human serum and Raji cells also showed an increase in immunosuppressive function, as determined by their inhibitory effect on PHA-induced GrzB expression by autologous CD8+ T cells (*p=0.0029) (Fig. 2).unmodified or complement-inactivated humanunmodified or complement-inactivated human We conclude that complement enhances generation of Treg cells induced by B lymphoma cells as indicated by both phenotypic and functional studies. Ongoing studies are exploring the role of individual complement components in Treg induction, and the possibility of using complement depletion as a strategy to boost immune responses against lymphoma. Disclosures: No relevant conflicts of interest to declare.

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MHC-I-Induced Apoptosis in Human B-Lymphoma Cells Is Dependent on Protein Tyrosine and Serine/Threonine Kinases

Experimental Cell Research ◽

10.1006/excr.1999.4571 ◽

1999 ◽

Vol 251 (1) ◽

pp. 128-134 ◽

Cited By ~ 8

Author(s):

Anders Elm Pedersen ◽

Søren Bregenholt ◽

Britta Johansen ◽

Søren Skov ◽

Mogens Helweg Claesson

Keyword(s):

Lymphoma Cells ◽

Mhc I ◽

B Lymphoma ◽

Protein Tyrosine ◽

B Lymphoma Cells ◽

Threonine Kinases ◽

Induced Apoptosis

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Survival signals within the tumour microenvironment suppress drug-induced apoptosis: lessons learned from B lymphomas.

Endocrine Related Cancer ◽

10.1677/erc.0.0060021 ◽

1999 ◽

pp. 21-23 ◽

Cited By ~ 22

Author(s):

S T Taylor ◽

J A Hickman ◽

C Dive

Keyword(s):

Lessons Learned ◽

Interleukin 4 ◽

Lymphoma Cells ◽

Drug Induced ◽

B Lymphoma ◽

B Lymphoma Cells ◽

Induced Apoptosis ◽

Receptor Ligation ◽

Survival Signals

The suppression of apoptosis is one mechanism by which tumours become drug resitant. Extracellular signals from the germinal centre (GC) of secondary lymphoid tissue can rescue B cells from physiological- and chemotherapy-induced apoptosis. Such survival signals include CD40 receptor ligation, interleukin-4 (IL-4) receptor stimulation and the interaction of the integrin ligand VCAM-1 with its receptor. The GC environment was modelled in vitro by providing B lymphoma cells with these survival signals. JLP119 B lymphoma cells underwent apoptosis after exposure to the topisomerase II inhibitor etoposide and this was dramatically reduced when the cells were cultured in the GC system. CD40 receptor ligation resulted in increased levels of Bcl-XL. Etoposide diminished the binding between Bax and Bcl-XL but this was restored by IL-4 and VCAM-1 triggered signals. These data demonstrate combined effects of three microenvironmental signals on the Bcl-2 family and illustrate the potential importance of such signalling pathways in drug resistance of tumour cells.

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