Upregulation of mdr1 gene is related to activation of the MAPK/ERK signal transduction pathway and YB-1 nuclear translocation in B-cell lymphoma

2011 ◽  
Vol 39 (5) ◽  
pp. 558-569 ◽  
Author(s):  
Huiling Shen ◽  
Wenlin Xu ◽  
Wenjuan Luo ◽  
Leilei Zhou ◽  
Wei Yong ◽  
...  
Keyword(s):  
Signal Transduction ◽  
B Cell ◽  
Nuclear Translocation ◽  
Cell Lymphoma ◽  
Signal Transduction Pathway ◽  
B Cell Lymphoma ◽  
Mdr1 Gene ◽  
Transduction Pathway

scholarly journals Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma

2012 ◽  
Vol 26 (1) ◽  
pp. 106-114 ◽  
Author(s):  
Seung-Cheol Lee ◽  
Michal Marzec ◽  
Xiaobin Liu ◽  
Suzanne Wehrli ◽  
Kanchan Kantekure ◽  
...  
Keyword(s):  
Signal Transduction ◽  
B Cell ◽  
Cell Lymphoma ◽  
Lactate Concentration ◽  
Signal Transduction Pathway ◽  
B Cell Lymphoma ◽  
Glycolytic Enzyme ◽  
Transduction Pathway ◽  
Enzyme Expression

scholarly journals The human B-cell lymphoma cell line RC-K8 has multiple genetic alterations that dysregulate the Rel/NF-κB signal transduction pathway

Oncogene ◽  
2002 ◽  
Vol 21 (57) ◽  
pp. 8759-8768 ◽  
Author(s):  
Demetrios Kalaitzidis ◽  
R Eric Davis ◽  
Andreas Rosenwald ◽  
Louis M Staudt ◽  
Thomas D Gilmore
Keyword(s):  
Signal Transduction ◽  
B Cell ◽  
Cell Line ◽  
Cell Lymphoma ◽  
Signal Transduction Pathway ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Lymphoma Cell Line ◽  
Transduction Pathway ◽  
Human B Cell

Effective treatment of aggressive B-cell lymphomas by downregulated NIK-induced noncanonical NF-κB pathway activation through inhibition of BAFF.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13554-e13554
Author(s):  
Sung Hsin Kuo ◽  
Li-Tzong Chen ◽  
Kun-Huei Yeh ◽  
Hui-Jen Tsai ◽  
Hsiao-Wei Lee ◽  
...  
Keyword(s):  
B Cell ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Nuclear Translocation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Luciferase Assay ◽  
Aggressive B Cell Lymphoma

e13554 Background: We recently reported that autocrine BAFF (B cell–activating factor belonging to the TNF family) signal transduction pathway contributes to H. pylori-independent growth of gastric diffuse large B-cell lymphoma (DLBCL) (Blood 2008;112:2927-34; Ann Hematol 2010;89:431-6). In this study, we sought to investigate whether activation of BAFF signaling pathway can promote the survival and proliferation of aggressive B-cell lymphoma. Methods: Seven aggressive NHL cell lines (EBV-negative Burkitt’s lymphoma (Ramos), EBV-positive Burkitt’s lymphoma (Raji), EBV-negative undifferentiated lymphoma (MC116), activated B cell (ABC)-like DLBCL (OCI-Ly3, OCI-Ly10), and germinal center B cell (GCB)-like DLBCL (OCI-Ly7, and Pfeiffer) were used in this study. Cell cycle was analyzed by flow cytometry. The DNA-binding activity of NF-kB was determined by the luciferase assay. Expression of non-canonical NF-κB signatures-related proteins (BAFF, BAFF-R, NIK, cIAP1, TRAF2, cIAP1/2, TRAF3, IKKa, p100, p52 and RelB, BCL10, BCL3, and STAT3) was assessed by immunoblotting. Results: Our results showed that in GCB-DLBCL cell lines, activation of BAFF induced recruitment and degradation of TRAF3, which resulted in NIK kinase accumulation, BCL10 Ser138 phosphorylation, IKKa phosphorylation, and NF-kB p100 processing, thereby resulting in continuous activation of non-canonical NF-kB pathway. This phenomenon also resulted in BCL3 nuclear translocation and STAT3 activation, and subsequently activated STAT3 downstream-regulated genes (BCL2, survivin, and cyclin D1). Furthermore, we found that inhibition of BAFF by short hairpin RNA (shRNA) suppressed the growth of ABC-DLBCL cells and Burkitt lymphoma cells through the down-regulation of BAFF/BAFF-R/TRAF3/NIK/BCL3/NF-kB signaling pathway. Conclusions: Our results indicate that constitutive BAFF signaling activates NIK-induced non-canonical NF-kB signaling pathway in aggressive B-cell lymphoma, and inhibition of BAFF is particularly effective in the treatment of this subgroup of tumors.

Overexpression of B cell–activating factor of TNF family (BAFF) is associated with Helicobacter pylori–independent growth of gastric diffuse large B-cell lymphoma with histologic evidence of MALT lymphoma

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2927-2934 ◽  
Author(s):  
Sung-Hsin Kuo ◽  
Pei-Yen Yeh ◽  
Li-Tzong Chen ◽  
Ming-Shiang Wu ◽  
Chung-Wu Lin ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
B Cell ◽  
Nuclear Translocation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Histologic Evidence ◽  
Nuclear Expression ◽  
B Cell Activating Factor ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract We have recently demonstrated that nuclear expression of BCL10 predicts Helicobacter pylori (HP) independence of early-stage gastric diffuse large B-cell lymphoma (DLBCL) with histologic evidence of mucosa-associated lymphoid tissue (MALT). In this study, we examined the role of B cell–activating factor of TNF family (BAFF) in mediating BCL10 nuclear translocation and HP independence of gastric DLBCL (MALT). We used immunohistochemistry and immunoblotting to measure the expression of BAFF, pAKT, BCL3, BCL10, and NF-κB. Transactivity of NF-κB was measured by electromobility shift assay. In lymphoma samples from 26 patients with gastric DLBCL (MALT), we detected aberrant expression of BAFF in 7 of 10 (70%) HP-independent and in 3 of 16 (18.8%) HP-dependent cases (P = .015). BAFF overexpression was associated with pAKT expression (P = .032), and nuclear expression of BCL3 (P = .014), BCL10 (P = .015), and NF-κB (P = .004). In B-cell lymphoma Pfeiffer cells, BAFF activated NF-κB and AKT; the activated NF-κB up-regulated BCL10, and the activated AKT caused formation of BCL10/BCL3 complexes that translocated to the nucleus. Inhibition of AKT by LY294002 (a PI3K inhibitor) blocked BCL10 nuclear translocation, NF-κB transactivity, and BAFF expression. Our results indicate that autocrine BAFF signal transduction pathways may contribute to HP-independent growth of gastric DLBCL (MALT).

scholarly journals Targeting NF-κB with First in Class N-Quinoline Benzenesulfonamides (NQBS) Reveals Potent Activity in Models of Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4435-4435
Author(s):  
Matko Kalac ◽  
Michael Mangone ◽  
Alison Rinderspacher ◽  
Shi-Xian Deng ◽  
Luigi Scotto ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
B Cell ◽  
Cell Lines ◽  
Mechanism Of Action ◽  
Research Funding ◽  
Nuclear Translocation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract The first two authors contributed equally to this work Identifying pharmacologic strategies to inhibit the activation of NF-κB and its target genes has been a major research pursuit. To date, no direct inhibitors of the NF-κB subunits have been explored in the clinic. Based on the constitutive activation of NF-κB in diffuse large B-cell lymphoma (DLBCL), we used this disease model to develop drugs targeting NF-κB. Using a fluorescence-based high throughput screening (HTC) approach, a unique N-quinoline-benzenesulfonamide (NQBS) scaffold was identified as potential small molecule inhibitor of the NF-κB pathway. A confocal microscopy based HTC assay performed in human umbilical vein endothelial cells (HUVEC) identified hit compounds that contained a unique NQBS core structure. The assay screened for compounds that inhibited nuclear translocation of NF-κB subunits in TNFα-induced HUVEC cells. To date over 100 NQBS analogs have been synthesized with varying potency and cytotoxicity in inhibiting growth of DLBCL lines (OCI-Ly10, RIVA, HBL-1 and OCI-Ly3). Cytotoxicity assays demonstrated that the most potent compounds exhibit IC50s in the 0.5 to 1.5 µM range. These most potent NQBS analogs identified as CU-O42 CU-O47 and CU-O75 were also able to induce apoptosis and caspase activation. Apoptosis was preceded by exclusion of the NF-κB proteins from the nucleus. To analyze the localization of NF-κB proteins within the cell compartments before and after the treatment with CU-O42, CU-O47 and CU-O75, we used confocal microscopy, electromobility shift (EMSA) and ELISA assays. Control cells tested positive for p50/p65 both within the cytoplasm and the nucleus. Following treatment with CU-O42 NF-κB was sequestered within the cytoplasm of the cell which occurred as early as 3h after exposure. In addition, all three analogs reduced the nuclear levels of NF-κB in a concentration-dependent manner when measured by EMSA and ELISA. Furthermore, CU-O47 and CU-O75 were able to inhibit TNFα induced luciferase expression in a HEK293T cell model where luciferase is controlled by an NF-κB promoter. A KINOMEscan platform (examining the activity of over 450 different kinases) showed that no NQBS analog screened (CU-O42 and CU-O75) inhibited any of the kinases in the assay. In addition, a proteasome inhibition assay tested negative for trypsin-like and chromotrypsin-like protease activity (CU-O42, CU-O47 and CU-O75). Stabilization of the inactive trimer of p50, p65 and IκBα was hypothesized as a potential mechanism of action of CU-O42 and CU-O75 through Internal Coordinate Mechanics (ICM) software. This binding hypothesis was further corroborated by cellular thermal shift assays (CETSA) with an increase of the IκBα melting temperatures (2.5-3°C) in whole cell lysates following rapid (30min) exposure to CU-O42 and CU-O75. Using a genome-wide regulatory network perturbation analysis (DeMAND) based on the RNA-Seq data collected from OCI-Ly10 cells treated with CU-O75, we identified IκBα as one of the potential targets of the compounds. Gene set enrichment analysis demonstrated NF-κB target gene downregulation using IC20 of CU-O75 at 24h (p=0.045). In vivo experiments were conducted in two models: (1) xenografts with human DLBCL cell lines of both ABC and GC subtype; and (2) myc cherry luciferase mouse model where mice spontaneously develop aggressive lymphomas. In both models, CU-O42 was able to inhibit tumor growth. Interestingly, in the xenograft model, malignant cell growth was inhibited in both ABC (HBL-1) and GC (OCI-Ly1) cells when compared to controls (p=0.01 and p=0.02). However, overall survival of mice with ABC xenografts treated with CU-042 significantly exceeded the survival of mice with GC xenografts (p<0.01) suggesting a more sustainable response in this subtype of disease, consistent with its dependency on NF-κB. Identification of a unique NQBS scaffold has led to the chemical synthesis of over 100 structural analogs with a potent inhibition on NF-κB nuclear translocation. They display potent activity across a panel of lymphoma cell lines, producing a survival benefit in mice implanted with an ABC-subtype of lymphoma. ICM, CETSA and DeMAND suggest that this is a direct effect mediated on the proteins within the p65/p50/IκBα complex. These findings point to a novel mechanism of action and warrant further research into potential clinical translation of this class of small molecules. Disclosures Califano: Thermo Fischer Scientific: Consultancy; Ipsen pharmaceuticals: Consultancy; Cancer Genetics Inc: Consultancy; Therasis Inc: Employment. O'Connor:Spectrum Pharmaceuticals: Consultancy, Honoraria, Research Funding; Takeda Millennium: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb Company: Consultancy; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy; Bayer: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding; Acetylon Pharmaceuticals, INC: Consultancy.

scholarly journals Evodiamine Mitigates Cellular Growth and Promotes Apoptosis by Targeting the c-Met Pathway in Prostate Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1320 ◽  
Author(s):  
Sun Tae Hwang ◽  
Jae-Young Um ◽  
Arunachalam Chinnathambi ◽  
Sulaiman Ali Alharbi ◽  
Acharan S. Narula ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Protein Kinase ◽  
B Cell ◽  
Nuclear Translocation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cellular Growth ◽  
Stat3 Phosphorylation ◽  
Du145 Cells

Evodiamine (EVO) is an indoloquinazoline alkaloid that exerts its various anti-oncogenic actions by blocking phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), c-Met, and nuclear factor kappa B (NF-κB) signaling pathways, thus leading to apoptosis of tumor cells. We investigated the ability of EVO to affect hepatocyte growth factor (HGF)-induced c-Met/Src/STAT3 activation cascades in castration-resistant prostate cancer (CRPC). First, we noted that EVO showed cytotoxicity and anti-proliferation activities in PC-3 and DU145 cells. Next, we found that EVO markedly inhibited HGF-induced c-Met/Src/STAT3 phosphorylation and impaired the nuclear translocation of STAT3 protein. Then, we noted that EVO arrested the cell cycle, caused apoptosis, and downregulated the expression of various carcinogenic markers such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), cyclin D1, cyclooxygenase 2 (COX-2), survivin, vascular endothelial growth factor (VEGF), and matrix metallopeptidases 9 (MMP-9). Moreover, it was observed that in cPC-3 and DU145 cells transfected with c-Met small interfering RNA (siRNA), Src/STAT3 activation was also mitigated and led to a decrease in EVO-induced apoptotic cell death. According to our results, EVO can abrogate the activation of the c-Met/Src/STAT3 signaling axis and thus plays a role as a robust suppressor of tumor cell survival, proliferation, and angiogenesis.

A Phase I Study Of The Oral Btk Inhibitor ONO-4059 In Patients With Relapsed/Refractory B-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4397-4397 ◽  
Author(s):  
Simon Rule ◽  
Nimish Shah ◽  
Gilles Andre Salles ◽  
Lionel Karlin ◽  
Franck Morschhauser ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoid Cells ◽  
Flat Dose ◽  
Btk Inhibitor

Abstract Introduction The B-cell receptor (BCR) pathway plays a central role in signal transduction pathways that regulate survival, activation, proliferation and differentiation of B-lineage lymphoid cells. Bruton’s tyrosine kinase (Btk) is a critical kinase in BCR signal transduction and recent studies support that targeting Btk is effective in the treatment of B-cell malignancies. ONO-4059 is a highly potent and selective oral Btk inhibitor with an IC50 in the sub-nmol/L range that has demonstrated anti-tumour activity in several pre-clinical models (Yasuhiro T et al, AACR 2013). Methods This Phase I study was initiated to determine the safety, tolerability, dose-limiting toxicity (DLT), pharmacokinetics and pharmacodynamics of ONO-4059 given as monotherapy to patients with relapsed/refractory NHL for whom no therapy of higher priority was available. In this safety-driven, dose-escalating 3+3 design, ONO-4059 was administered as an oral, daily dose (flat dose) given continuously initially for up to 6 months, with the option of additional dosing up to 2 years. We present the safety and efficacy data on 14 evaluable patients (mantle cell lymphoma n=7, follicular lymphoma n=3, plasmablastic DLBCL n=1, ABC-DLBCL n=1, small lymphocytic lymphoma n=1 and Waldenstrom’s macroglobulinaemia n=1), with a median age 64 yrs (range 48-88), median baseline tumour burden 5,668 mm2 [1,582-19,509]. Patients received a median of 3 prior therapies [range 2-8], with all patients having prior exposure to a rituximab-containing regimen 93% (13/14) and 29% of patients (4/14) had prior ASCT. Patients received ONO-4059 at doses ranging from 20mg-160mg (cohorts 1-4) and the study is currently ongoing with additional dose escalation cohorts to be completed. Results ONO-4059 was found to be well tolerated, with no dose limiting toxicities (DLTs). A total of 18 ONO-4059-related adverse events were reported in 6 out of 14 patients; CTCAE-V4.0 G1 (n=10 [n=6 in 1 patient]) and G2 (n=5). Three ONO-4059-related G3 haematological toxicities were reported in 2 patients; thrombocytopenia (x2) and anemia. No ONO-4059-related G4 events, or related SAEs or infections were reported. The pharmacokinetics of ONO-4059 reflects rapid absorption and elimination, a half-life of ∼6 hours, a dose dependent increase in exposure with no accumulation of ONO-4059 exposure and low inter- or intra-patient variability; with Btk occupancy in peripheral blood (as measured by phosphorylated Btk) being maintained for at least 24 hours across all dose levels. Responses have occurred at doses of 40, 80 and 160mg, with a best overall response rate of 42% [based on CT-scan and physical examination for 5/12 evaluable patients]; with 5 PR, 4 SD, 2 PD (both MCL) and one ABC-DLBCL patient was withdrawn due to non-related SAE during Cycle 1. Of the 6 evaluable MCL patients, 3 have achieved PR resulting in a best ORR of 50% (median reduction of lymph nodes was 73% [45%-84%]). Almost all patients experienced clinically meaningful rapid reductions in lymphadenopathy observed within the first cycle. Ten of the fourteen patients are currently still on study with a median progression-free survival of 93.5 days [Range 8-268]. In conclusion, ONO-4059 is a highly potent and selective oral Btk inhibitor that shows a favourable safety profile along with promising efficacy in this difficult-to-treat patient population. Disclosures: Salles: Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Karlin:Janssen: Honoraria; Celgene: Honoraria. Morschhauser:ONO Pharma: Honoraria; Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Dyer:Ono Pharma: Honoraria, Research Funding. Hutchinson:Ono Pharma: Research Funding. Fegan:ONO Pharma: Honoraria. Cartron:ONO Pharma: Honoraria. Knurowski:ONO Pharma: Consultancy. Wright:ONO Pharma: Consultancy. Saunders:ONO Pharma: Consultancy; Pharmacyclics: Consultancy. Honda:ONO Pharma: Employment. Mazur:ONO Pharma: Consultancy. Yoshizawa:Ono Pharma: Employment. Kawabata:Ono Pharmaceutical Co., Ltd.: Employment. Birkett:Ono Pharma UK: Employment.

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