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The NF-?B Activating Pathways in Multiple Myeloma.

ABSTRACT: Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF-?B) family of transcription factors has been implicated in the pathogenesis of multiple myeloma. Tumor microenvironment-derived cytokines and cancer-associated genetic mutations signal through the canonical as well as the non-canonical arms to activate the NF-?B system in myeloma cells. In fact, frequent engagement of both the NF-?B pathways constitutes a distinguishing characteristic of myeloma. In turn, NF-?B signaling promotes proliferation, survival and drug-resistance of myeloma cells. In this review article, we catalog NF-?B activating genetic mutations and microenvironmental cues associated with multiple myeloma. We then describe how the individual canonical and non-canonical pathways transduce signals and contribute towards NF-?B -driven gene-expressions in healthy and malignant cells. Furthermore, we discuss signaling crosstalk between concomitantly triggered NF-?B pathways, and its plausible implication for anomalous NF-?B activation and NF-?B driven pro-survival gene-expressions in multiple myeloma. Finally, we propose that mechanistic understanding of NF-?B deregulations may provide for improved therapeutic and prognostic tools in multiple myeloma.

SUBMITTER: Roy P

PROVIDER: S-EPMC6027071 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The NF-κB Activating Pathways in Multiple Myeloma.

Roy Payel P Sarkar Uday Aditya UA Basak Soumen S

Biomedicines 20180516 2

Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF-κB) family of transcription factors has been implicated in the pathogenesis of multiple myeloma. Tumor microenvironment-derived cytokines and cancer-associated genetic mutations signal through the canonical as well as the non-canonical arms to activate the NF-κB system in myeloma cells. In fact, frequent engagement of both the ...[more]

PMID: 29772694

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Project description:ObjectiveAs an important negative regulatory factor of immunological cells, Tim3 plays a regulating role in tumor immune microenvironment. The purpose of this study was to investigate the expression of Tim3 on MM cells and its effect on the proliferation and apoptosis of MM cells, as well as its potential mechanism.MethodsIn this study, the expression of Tim3 was detected on myeloma cells (CD38+CD138+ cells) of bone marrow by flow cytometry (FCM) from 167 patients with MM and 51 healthy donors as controls and making correlation analysis with related clinical indexes. In vitro, MM cell lines (RPMI-8226 and U266) were treated with Tim3 knock-down alone, bortezomib alone and combination of Tim3 knock-down and bortezomib, then cell proliferation, cell apoptosis and downstream signaling pathway were detected by CCK-8, FCM, RT-PCR and western blot.ResultsThe expression of Tim3 on myeloma cells in MM patients was significantly higher than normal control group and positively correlated with β2 microglobulin, creatine, and plasma cells of bone marrow, negatively correlated with hemoglobin and red blood cells. In vitro, we validated the high expression of Tim3 in RPMI-8226 and U266 cell lines. After Tim3 knock-down, the cell proliferation was inhibited and cell apoptosis was induced, the relative mRNA and protein expression of Tim3 and NF-κB signal pathway (PI3K, AKT, mTOR, NF-κB) were significantly decreased. Also, the cell proliferation was inhibited, cell apoptosis was increased, the relative mRNA and protein expression of NF-κB were decreased significantly in combination group than bortezomib or Tim3 knock-down group.ConclusionsThe high expression of Tim3 on MM cells is associated with progression of MM patients. Tim3 maybe regulate the proliferation of MM cells via NF-κB signal pathway. Down-regulation of Tim3 expression can inhibit proliferation and induce apoptosis of MM cells, also has an additive inhibitory effect of bortezomib on NF-κB signaling pathway, then inhibit proliferation and induce apoptosis. Therefore, Tim3 may be a potential target for the treatment of MM.

Dataset Information

The NF-?B Activating Pathways in Multiple Myeloma.

Publications

The NF-κB Activating Pathways in Multiple Myeloma.

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