Investigating the Role of the Inhibitor of Apoptosis Proteins (IAPs) in Metastasis Formation

Majorini, Maria Teresa (2018). Investigating the Role of the Inhibitor of Apoptosis Proteins (IAPs) in Metastasis Formation. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000ce90

Abstract

Inhibitor of apoptosis proteins (IAPs) constitute a conserved family of molecules, which regulate both apoptosis and receptor signalling. They are often deregulated in cancer cells and represent potential targets for therapy. In my work, I investigated the effect of IAP inhibition in vivo to identify novel down-stream 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 (TNBC) cell line MDA-MB231 were treated with SM83, a Smac mimetic developed in our laboratory that acts as a pan-IAP inhibitor, and tumour nodules were profiled for gene expression. The analysis revealed that the inhibition of IAPs significantly reduces the expression of SNAI2, a zinc finger transcriptional repressor often associated with cancer aggressiveness, resistance to therapy and metastatic potential, especially in breast cancer. By testing several TNBC cell lines, I found that SNAI2 levels is promoted specifically by cellular IAP1 (cIAP1), and not by other IAPs, and that SM83-dependent down-regulation of SNAI2 reduces cancer cell motility. Accordingly, cIAP1 depletion blocks epidermal growth factor receptor (EGFR)-dependent activation of the mitogen-activated protein kinase (MAPK) pathway causing the reduction of SNAI2 transcription levels. The inhibition of EGFR signalling stems from the block of receptor signalling and from the down-regulation of its levels, but paradoxically the silencing of cIAP1 promotes EGFR stability rather than its degradation. Nonetheless, EGFR levels decrease upon cIAP1 silencing due to reduced NF-kB-dependent gene expression supporting the notion that cIAP1 controls EGFR in an opposite fashion, promoting its gene expression while causing its degradation. In conclusion, my work indicates that IAP-targeted therapy could contribute to EGFR inhibition and to the reduction of its down-stream mediators. This approach could be particularly effective in tumours characterized by high levels of EGFR and SNAI2, such as TNBCs.

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