cIAP1 ligand 2 - CAS 2357114-70-4

Receptor activator of nuclear factor κB (RANK) is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and triggers osteoclastogenesis by inducing the expression of NFATc1 through the activation of the NF-κB and MAPK pathways. Cellular inhibitors of apoptosis proteins 1 and 2 (cIAP1/2), which are ubiquitin E3 ligases, are involved in the activation of the NF-κB and MAPK pathways by various members of the TNFRSF. However, the involvement of cIAP1/2 in RANK signaling has remained largely unknown. In this study, we reveal the involvement of cIAP1/2 in RANK ligand (RANKL)-induced osteoclastogenesis. The over-expression of cIAP1 or cIAP2 in the mouse monocytic cell line Raw264.7 resulted in the significant suppression of RANKL-induced NFATc1 mRNA expression and osteoclastogenesis, whereas the activation of the NF-κB and MAPK pathways was barely changed by these over-expressions. The depletion of endogenous cIAP1/2 by their specific inhibitor MV1 or their siRNA-mediated knockdown resulted in enhanced RANKL-induced NFATc1 expression and osteoclastogenesis without affecting the activation of the NF-κB and MAPK pathways. In combination, these results indicate that cIAP1/2 negatively regulate osteoclastogenesis by inhibiting NFATc1 mRNA expression in a manner that is distinct from the previously identified functions of cIAP1/2.

Head and neck squamous cell carcinomas (HNSCCs) frequently harbor genomic mutations in cell death pathways. Nearly 30% of HNSCCs overexpress Fas-Associated Death Domain (FADD), with or without BIRC2/3 genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2), critical components of the Tumor Necrosis Factor (TNF) Receptor signaling pathways. ASTX660 is a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP under evaluation in a clinical trial for advanced solid tumors and lymphomas. Herein, we show that ASTX660, at nanomolar concentrations, sensitized Murine Oral Cancer (MOC1) cells to TNFα. Using syngeneic mouse models, ASTX660 showed additive anti-tumor activity with radiation therapy (XRT), cisplatin chemotherapy, and PD-1 blockade to significantly delay or eradicate MOC1 tumors. These combinations significantly increased CD8 + T cells and dendritic cells, as well as T cell activity. ASTX660 stimulated cytotoxic T lymphocyte (CTL) killing of MOC1 cells expressing ovalbumin. Early stages of CTL killing were predominantly mediated by perforin/granzyme B, whereas later stages were mediated by death ligands TNFα, TRAIL, and FasL. Correspondingly, depletion of CD8 + T cells and NK cells in vivo revealed both types of immune cells to be important components of the complete anti-tumor response enhanced by ASTX660+XRT. These findings serve to inform future studies of IAP inhibitors and support the potential for future clinical trials investigating ASTX660 with XRT and immunotherapies like PD-1/PD-L1 blockade in HNSCC.

Background:The sigma-2 receptor has been validated as a biomarker for proliferating tumours. Second mitochondria-derived activator of caspase (Smac) is a protein released from mitochondria into the cytosol, leading to apoptosis. In this study, we investigated a sigma-2 ligand as a tumour-targeting drug delivery agent for treating ovarian cancer.