Antagonizing binding of cell cycle and apoptosis regulatory protein 1 (CARP-1) to the NEMO/IKK? protein enhances the anticancer effect of chemotherapy.
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ABSTRACT: 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.
SUBMITTER: Venkatesh J
PROVIDER: S-EPMC7076213 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
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