B Cell Lymphoma 2: A Potential Therapeutic Target for Cancer Therapy

Defects in the apoptosis mechanism stimulate cancer cell growth and survival. B cell lymphoma 2 (Bcl-2) is an anti-apoptotic molecule that plays a central role in apoptosis. Bcl-2 is the founding constituent of the Bcl-2 protein family of apoptosis controllers, the primary apoptosis regulators linked with cancer. Bcl-2 has been identified as being over-expressed in several cancers. Bcl-2 is induced by protein kinases and several signaling molecules which stimulate cancer development. Identifying the important function played by Bcl-2 in cancer progression and development, and treatment made it a target related to therapy for multiple cancers. Among the various strategies that have been proposed to block Bcl-2, BH3-mimetics have appeared as a novel group of compounds thanks to their favorable effects on many cancers within several clinical settings. Because of the fundamental function of Bcl-2 in the regulation of apoptosis, the Bcl-2 protein is a potent target for the development of novel anti-tumor treatments. Bcl-2 inhibitors have been used against several cancers and provide a pre-clinical platform for testing novel therapeutic drugs. Clinical trials of multiple investigational agents targeting Bcl-2 are ongoing. This review discusses the role of Bcl-2 in cancer development; it could be exploited as a potential target for developing novel therapeutic strategies to combat various types of cancers. We further highlight the therapeutic activity of Bcl-2 inhibitors and their implications for the therapeutic management of cancer.

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SYK, A NOVEL THERAPEUTIC TARGET FOR PTLD, DRIVES EPSTEIN BARR VIRUS (EBV)+ B CELL LYMPHOMA GROWTH AND SURVIVAL THROUGH ACTIVATION OF THE PI3K/AKT PATHWAY

Transplantation Journal ◽

10.1097/01.tp.0000332036.17315.6a ◽

2008 ◽

Vol 86 (Supplement) ◽

pp. 282

Author(s):

O Hatton ◽

S Lambert ◽

M Vaysberg ◽

J Sharman ◽

S M. Krams ◽

...

Keyword(s):

B Cell ◽

Therapeutic Target ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Akt Pathway ◽

Growth And Survival ◽

Barr Virus ◽

Epstein Barr ◽

Novel Therapeutic

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Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma

Haematologica ◽

10.3324/haematol.2016.163030 ◽

2017 ◽

Vol 102 (7) ◽

pp. 1247-1257 ◽

Cited By ~ 35

Author(s):

Richard A. Noble ◽

Natalie Bell ◽

Helen Blair ◽

Arti Sikka ◽

Huw Thomas ◽

...

Keyword(s):

B Cell ◽

Burkitt Lymphoma ◽

Therapeutic Approach ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Novel Therapeutic

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Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma

Blood ◽

10.1182/blood-2014-06-584524 ◽

2014 ◽

Vol 124 (13) ◽

pp. 2081-2090 ◽

Cited By ~ 37

Author(s):

Alexander Hoellein ◽

Mohammad Fallahi ◽

Stephanie Schoeffmann ◽

Sabine Steidle ◽

Franz X. Schaub ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Therapeutic Option ◽

B Cell Lymphoma ◽

Key Points ◽

Novel Therapeutic

Key Points The Myc oncoprotein targets central regulators of the SUMOylation machinery, resulting in a hyper-SUMOylation state in Myc-induced lymphoma. Targeting SUMOylation by genetic or pharmacologic means represents a novel therapeutic option for lymphomas with MYC involvement.

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Nuclear CD40 interacts with c-Rel and enhances proliferation in aggressive B-cell lymphoma

Blood ◽

10.1182/blood-2007-02-073080 ◽

2007 ◽

Vol 110 (6) ◽

pp. 2121-2127 ◽

Cited By ~ 39

Author(s):

Hai-Jun Zhou ◽

Lan V. Pham ◽

Archito T. Tamayo ◽

Yen-Chiu Lin-Lee ◽

Lingchen Fu ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Target Genes ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Promoter Activation ◽

Growth And Survival ◽

Survival Mechanisms ◽

Lymphoma Therapy ◽

Receptor Family

Abstract CD40 is an integral plasma membrane–associated member of the TNF receptor family that has recently been shown to also reside in the nucleus of both normal B cells and large B-cell lymphoma (LBCL) cells. However, the physiological function of CD40 in the B-cell nucleus has not been examined. In this study, we demonstrate that nuclear CD40 interacts with the NF-κB protein c-Rel, but not p65, in LBCL cells. Nuclear CD40 forms complexes with c-Rel on the promoters of NF-κB target genes, CD154, BLyS/BAFF, and Bfl-1/A1, in various LBCL cell lines. Wild-type CD40, but not NLS-mutated CD40, further enhances c-Rel–mediated Blys promoter activation as well as proliferation in LBCL cells. Studies in normal B cells and LBCL patient cells further support a nuclear transcriptional function for CD40 and c-Rel. Cooperation between nuclear CD40 and c-Rel appears to be important in regulating cell growth and survival genes involved in lymphoma cell proliferation and survival mechanisms. Modulating the nuclear function of CD40 and c-Rel could reveal new mechanisms in LBCL pathophysiology and provide potential new targets for lymphoma therapy.

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MLN4924, a Novel Small Molecule Inhibitor of Nedd8-Activating Enzyme, Demonstrates Potent Anti-Tumor Activity in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v112.11.606.606 ◽

2008 ◽

Vol 112 (11) ◽

pp. 606-606

Author(s):

Michael Milhollen ◽

Usha Narayanan ◽

Allison J Berger ◽

Michael Thomas ◽

Tary Traore ◽

...

Keyword(s):

Single Dose ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Growth And Survival ◽

Large B Cell Lymphoma ◽

Molecule Inhibitor ◽

Induction Of Apoptosis ◽

Pathway Inhibition ◽

Large B Cell

Abstract MLN4924 is a first-in-class, small molecule inhibitor of the Nedd8 Activating Enzyme (NAE) in Phase I clinical trials in hematological malignancies. Inhibition of NAE by MLN4924 leads to decreased neddylation and inhibition of cullin-dependent ubiquitin ligase (CDL) activity. CDLs are enzyme complexes which control the ubiquitination and degradation of proteins with important roles in cell cycle progression and cell survival. CDL-mediated degradation of pIkBa regulates NF-kB signaling by freeing cytoplasmic NF-kB transcription factors to translocate to the nucleus promoting cell proliferation and survival. In tumors dependent on the NF-kB pathway for growth and survival, we hypothesized that MLN4924 inhibition of CDL activity would prevent pIkBa degradation and inhibit NF-kB signaling. We utilized models of ABC-like Diffuse Large B-cell Lymphoma (ABC-like DLBCL, OCI-Ly10 and OCI-Ly3 cells) dependent on NF-kB signaling for survival and Germinal Center B-cell like DLBCL (GCB-like DLBCL, OCI-Ly19 and OCI-Ly7 cells) that are not dependent on NF-kB signaling for survival. In vitro, we show that NAE inhibition by MLN4924 in ABC-like DLBCL produces marked stabilization of pIkBa, inhibits p65 nuclear translocation and NF-KB gene transcription demonstrating an inhibition of NF-kB signaling. The inhibition of NF-KB signaling in Ly10 cells results in a G1 phenotype and an acute induction of apoptosis. In contrast, in GCB-like DLBCL we observed an elevation of multiple substrates of the CDLs, an accumulation of cells with increased DNA content (>4N) followed by a DNA damage response and induction of cell death. This mechanism of action in GCB-like DLBCL cells is observed in other tumor cell lines that are not dependent on NF-kB signaling for survival. In vivo administration of MLN4924 to mice bearing xenograft tumors of OCI-Ly10 and OCI-Ly19 resulted in a pharmacodynamic response of NAE pathway inhibition. In both models, a single dose of MLN4924 resulted in time and dose-dependent inhibition of total neddylated cullin levels and stabilization of CDL substrates including the CDL3Keap1 substrate, Nrf-2. Notably, in the OCI-Ly10 model, a single dose of MLN4924 resulted in a marked elevation of pIkBa levels, indicative of NF-kB pathway inhibition, and induction of apoptosis. In both OCI-Ly10 and OCI-Ly19 xenograft models, inhibition of the NAE pathway following repeated daily and intermittent dosing of MLN4924 translated into significant tumor growth inhibition. In the OCI-Ly10 model tumor regressions were observed showing this model to be particularly sensitive to MLN4924 treatment, reflecting the addiction of these tumors to NF-kB signaling. Additionally we demonstrate an inhibition of the NAE pathway and NF-KB signaling in a primary human tumor DLBCL xenograft model (PHTX-22L) resulting in tumor regressions following MLN4924 treatment. In summary, in tumors dependent on NF-kB signaling for growth and survival, MLN4924 inhibition of CDL activity provides a novel mechanism for targeted NF-kB pathway modulation and therapeutic intervention. In addition, these data demonstrate that MLN4924 is a novel agent that has broad activity in pre-clinical models of lymphoma.

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Erratum: B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway

Oncogene ◽

10.1038/onc.2017.250 ◽

2017 ◽

Vol 36 (38) ◽

pp. 5440-5440 ◽

Cited By ~ 3

Author(s):

T-S Wu ◽

C-T Tan ◽

C-C Chang ◽

B-R Lin ◽

W-T Lai ◽

...

Keyword(s):

Oral Cancer ◽

B Cell ◽

Signaling Pathway ◽

Cancer Progression ◽

Cell Lymphoma ◽

B Cell Lymphoma

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A Systematical Review of The Effect of Ketogenic Diet on Bcl-2 (B-cell lymphoma-2) Expression as An Apoptosis Marker in Cancer Treatment

Biomolecular and Health Science Journal ◽

10.20473/bhsj.v4i2.30173 ◽

2021 ◽

Vol 4 (2) ◽

pp. 130

Author(s):

Vania Islamey Kusuma ◽

Reny I’tishom ◽

Ema Qurnianingsih ◽

Purwo Sri Rejeki

Keyword(s):

B Cell ◽

Ketogenic Diet ◽

Cancer Progression ◽

Protein Level ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Total Sample ◽

Control Group ◽

P Value ◽

High Fat

Introduction: Ketogenic diet seems to be in a great demand nowadays as a lot of people are interested in adopting it into their lifestyle. It is also found that the ketogenic diet shows several beneficial effects including cancer prevention. However, the detail mechanism still remains unknown. Therefore, this review was aimed to find out the effect of ketogenic diet on Bcl-2 (B-cell lymphoma-2) expression in cancer.Methods: We searched published literatures in PubMed through 2011-2020 using specific keywords. The literatures were filtered according to inclusion and exclusion criteria. Animal model, total sample size, underlying condition/inflammatory process occurs, details of the intervention/diet including diet contents in control group and high-fat group, and the duration of the intervention, Bcl-2 results, and p-value were extracted.Results: 7 studies were included in this review. Bcl-2 expression found decrease in 5 out of 6 studies. Similar result also obtained in Bcl-2 protein level, which measured by western blot. Bcl-2 protein level shows a decrease in 2 out of 3 studies.Conclusion: This review shows that high-fat diet that contained in ketogenic diet most likely lead to decrease in Bcl-2 expression. Therefore, indicating the ability of ketogenic diet to affect cancer progression by inducing apoptosis process.

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Long non‐coding RNA DBH‐AS1 promotes cancer progression in diffuse large B‐cell lymphoma by targeting FN1 via RNA‐binding protein BUD13

Cell Biology International ◽

10.1002/cbin.11327 ◽

2020 ◽

Vol 44 (6) ◽

pp. 1331-1340 ◽

Cited By ~ 4

Author(s):

Yanping Song ◽

Feng Gao ◽

Yi Peng ◽

Xuejie Yang

Keyword(s):

B Cell ◽

Cancer Progression ◽

Rna Binding ◽

Cell Lymphoma ◽

Rna Binding Protein ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Non Coding Rna ◽

Long Non Coding Rna ◽

Large B Cell

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The Combination Of 2-DG and Metformin Inhibits The mTORC1 Pathway and Suppresses Aggressive B Cell Lymphoma Growth and Survival

Blood ◽

10.1182/blood.v122.21.1665.1665 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1665-1665 ◽

Cited By ~ 2

Author(s):

Chengfeng Bi ◽

Kai Fu ◽

Chunsun Jiang ◽

Xin Huang ◽

Wing Chung Chan ◽

...

Keyword(s):

Cell Growth ◽

B Cell ◽

Conflicts Of Interest ◽

Cell Lymphoma ◽

Combined Treatment ◽

Control Cell ◽

B Cell Lymphoma ◽

Protein Translation ◽

Growth And Survival ◽

Aggressive B Cell Lymphoma

Abstract mTORC1 (mammalian target of rapamycin complex 1) plays a central role in integrating nutrient and growth factor inputs to control cell growth in all eukaryotes and is commonly deregulated in human cancers. Inhibition of mTORC1 is a promising strategy in lymphoma therapy. However, only a few drugs, such as rapamycin and its analogs (rapalogs), have been approved for treatment in a limited number of cancer types, due to their incomplete and nonspecific inhibition of mTORC1 as well as their limited effects toward the 4EBP1 pathway. 4EBP1 pathway regulates protein translation which is considered to be crucial in cancer cell survival and proliferation. In this study, we used the glycolysis inhibitor 2-deoxyglucose (2-DG) together with the mitochondrial respiratory inhibitor metformin to treat aggressive B cell lymphoma cells in vitro and in vivo. We found that the combined treatment inhibited mTORC1 and its major downstream targets, including 4EBP1. As a result, combined treatment significantly inhibited tumor cell growth and survival by the inhibition of 5’ cap-dependent translation involving lymphoma associated oncogenes such as MCL-1, BCL-XL and Cyclin D1. Moreover, the combination of 2-DG and metformin suppressed tumor growth in B cell lymphoma xenograft mouse models. Although the combined treatment dramatically decreased cellular ATP levels, mTORC1 inhibition was independent of AMPK activity but instead resulted from inhibitory effects on Rag-GTPases, which are upstream activators of mTORC1. Given that both 2-DG and metformin have been used in clinical diagnosis or treatment for decades, the combination of the two drugs hold promise as a new strategy to treat aggressive B cell lymphoma. Disclosures: No relevant conflicts of interest to declare.

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