Antagonizing binding of cell cycle and apoptosis regulatory protein 1 (CARP-1) to the NEMO/IKK? protein enhances the anticancer effect of chemotherapy.
NF-?B is a pro-inflammatory transcription factor that critically regulates immune responses and other distinct cellular pathways. However, many NF-?B-mediated pathways for cell survival and apoptosis signaling in cancer remain to be elucidated. Cell cycle and apoptosis regulatory protein 1 (CARP-1 or CCAR1) is a perinuclear phosphoprotein that regulates signaling induced ... by anticancer chemotherapy and growth factors. Although previous studies have reported that CARP-1 is a part of the NF-?B proteome, regulation of NF-?B signaling by CARP-1 and the molecular mechanism(s) involved are unclear. Here, we report that CARP-1 directly binds the NF-?B-activating kinase I?B kinase subunit ? (NEMO or NF-?B essential modulator) and regulates the chemotherapy-activated canonical NF-?B pathway. Importantly, blockade of NEMO-CARP-1 binding diminished NF-?B activation, indicated by reduced phosphorylation of its subunit p65/RelA by the chemotherapeutic agent adriamycin (ADR), but not NF-?B activation induced by tumor necrosis factor ? (TNF?), interleukin (IL)-1?, or epidermal growth factor. High-throughput screening of a chemical library yielded a small molecule inhibitor of NEMO-CARP-1 binding, termed selective NF-?B inhibitor 1 (SNI)-1). We noted that SNI-1 enhances chemotherapy-dependent growth inhibition of a variety of cancer cells, including human triple-negative breast cancer (TNBC) and patient-derived TNBC cells in vitro, and attenuates chemotherapy-induced secretion of the pro-inflammatory cytokines TNF?, IL-1?, and IL-8. SNI-1 also enhanced ADR or cisplatin inhibition of murine TNBC tumors in vivo and reduced systemic levels of pro-inflammatory cytokines. We conclude that inhibition of NEMO-CARP-1 binding enhances responses of cancer cells to chemotherapy.
Mesh Terms:
Animals, Antineoplastic Agents, Apoptosis Regulatory Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Cisplatin, Cytokines, DNA Damage, Doxorubicin, Epitopes, I-kappa B Kinase, Inflammation Mediators, Kinetics, Mice, Inbred BALB C, Models, Biological, Models, Molecular, Phosphorylation, Protein Binding, Signal Transduction, Thermodynamics, Transcription Factor RelA
Animals, Antineoplastic Agents, Apoptosis Regulatory Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Cisplatin, Cytokines, DNA Damage, Doxorubicin, Epitopes, I-kappa B Kinase, Inflammation Mediators, Kinetics, Mice, Inbred BALB C, Models, Biological, Models, Molecular, Phosphorylation, Protein Binding, Signal Transduction, Thermodynamics, Transcription Factor RelA
J Biol Chem
Date: Dec. 13, 2019
PubMed ID: 32024692
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