| Autor: |
Venkatesh J; John D. Dingell Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Department of Oncology, Wayne State University, Detroit, Michigan 48201., Sekhar SC; John D. Dingell Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Department of Oncology, Wayne State University, Detroit, Michigan 48201., Cheriyan VT; John D. Dingell Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Department of Oncology, Wayne State University, Detroit, Michigan 48201., Muthu M; John D. Dingell Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Department of Oncology, Wayne State University, Detroit, Michigan 48201., Meister P; Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada., Levi E; John D. Dingell Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Department of Pathology, Wayne State University, Detroit, Michigan 48201., Dzinic S; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201., Gauld JW; Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada., Polin LA; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201., Rishi AK; John D. Dingell Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Department of Oncology, Wayne State University, Detroit, Michigan 48201. Electronic address: Rishia@Karmanos.org. |
| Abstrakt: |
NF-κB is a pro-inflammatory transcription factor that critically regulates immune responses and other distinct cellular pathways. However, many NF-κB-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-κB proteome, regulation of NF-κB signaling by CARP-1 and the molecular mechanism(s) involved are unclear. Here, we report that CARP-1 directly binds the NF-κB-activating kinase IκB kinase subunit γ (NEMO or NF-κB essential modulator) and regulates the chemotherapy-activated canonical NF-κB pathway. Importantly, blockade of NEMO-CARP-1 binding diminished NF-κB activation, indicated by reduced phosphorylation of its subunit p65/RelA by the chemotherapeutic agent adriamycin (ADR), but not NF-κB activation induced by tumor necrosis factor α (TNFα), interleukin (IL)-1β, or epidermal growth factor. High-throughput screening of a chemical library yielded a small molecule inhibitor of NEMO-CARP-1 binding, termed selective NF-κB 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 TNFα, IL-1β, 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. |
