cIAP1 regulates the EGFR/Snai2 axis in triple-negative breast cancer cells

Abstract

Inhibitor of apoptosis (IAP) proteins constitute a family of conserved molecules that regulate both apoptosis and receptor signaling. They are often deregulated in cancer cells and represent potential targets for therapy. In our work, we investigated the effect of IAP inhibition in vivo to identify novel downstream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple-negative breast cancer MDA-MB231 cell line were treated with SM83, a Smac mimetic that acts as a pan-IAP inhibitor, and tumor nodules were profiled for gene expression. SM83 reduced the expression of Snai2, an epithelial-to-mesenchymal transition factor often associated with increased stem-like properties and metastatic potential especially in breast cancer cells. By testing several breast cancer cell lines, we demonstrated that Snai2 downregulation prevents cell motility and that its expression is promoted by cIAP1. In fact, the chemical or genetic inhibition of cIAP1 blocked epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway and caused the reduction of Snai2 transcription levels. In a number of breast cancer cell lines, cIAP1 depletion also resulted in a reduction of EGFR protein levels which derived from the decrease of its gene transcription, though, paradoxically, the silencing of cIAP1 promoted EGFR protein stability rather than its degradation. Finally, we provided evidence that IAP inhibition displays an anti-tumor and anti-metastasis effect in vivo. In conclusion, our work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its downstream mediators. This approach could be particularly effective in tumors characterized by high levels of EGFR and Snai2, such as triple-negative breast cancer.

Structure‐based design and molecular profiling of Smac‐mimetics selective for cellular IAPs

“…We experimentally tested our hypothesis demonstrating the higher affinity for isolated BIR3 domains by 23-(SM114) and 32-(SM130) fold, respectively. Furthermore, in vitro cell-based assays revealed that both SM114 and SM130 are able to induce apoptosis in MDA-MB231 cells, like other SMs belonging to our library [16,20,34]. Finally, SMs selectivity was confirmed by the caspase-independent autodegradation of cIAPs.…”

“…Furthermore, in vitro cell-based assays revealed that both SM114 and SM130 are able to induce apoptosis in MDA-MB231 cells, like other SMs belonging to our library [16,20,34]. We then synthesized two SMs, SM114 exploiting position 292 and SM130 exploiting position 309, both predicted to have higher affinity for cIAP respect to XIAP.…”

SAHA and EGCG Promote Apoptosis in Triple-negative Breast Cancer Cells, Possibly Through the Modulation of cIAP2

“…With the combination of SAHA and EGCG, cIAP2 expression was reduced in the MDA-MB-157 and HCC1806 cell lines when compared to SAHA alone, though EGCG administered alone was able to reduce cIAP2 expression in the MDA-MB-231 cell line. We also found that the combination was successful in reducing cIAP2 protein levels in the MCF- inhibition of cIAP1 using a second mitochondrial activator of caspases (Smac) mimetic resulted in anticancer effects through the EGFR/Snai2 axis, which reduced tumor aggressiveness (29). Smac proteins activate apoptosis through neutralizing IAP proteins.…”

Bile acids increase intestinal markers via FXR/SNAI2/miR-1 axis in the stomach

“…SNAI2 (also known as Slug), a member of Snail superfamily, is one of the transcription factors of epithelial mesenchymal transition (EMT) [32]. In recent years, it has been found that SNAI2 is abnormally expressed in various kinds of malignant tumors and plays an important role in tumor progress and prognosis [33][34][35]. To investigate the role of SNAI2 in IM cells, we examined its expression level in IM tissues and BA-induced IM cells.…”