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cIAP1 regulates the EGFR/Snai2 axis in triple-negative breast cancer cells.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2018 Dec; Vol. 25 (12), pp. 2147-2164. Date of Electronic Publication: 2018 Apr 19. - Publication Year :
- 2018
-
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.
- Subjects :
- Administration, Intravenous
Animals
Antineoplastic Agents administration & dosage
Antineoplastic Agents pharmacology
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Female
Humans
Inhibitor of Apoptosis Proteins antagonists & inhibitors
Inhibitor of Apoptosis Proteins deficiency
Injections, Intraperitoneal
Mice
Mice, Inbred NOD
Mice, SCID
Oligopeptides administration & dosage
Oligopeptides pharmacology
Snail Family Transcription Factors antagonists & inhibitors
Snail Family Transcription Factors genetics
Triple Negative Breast Neoplasms drug therapy
Tumor Cells, Cultured
Inhibitor of Apoptosis Proteins metabolism
Snail Family Transcription Factors metabolism
Triple Negative Breast Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 25
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 29674627
- Full Text :
- https://doi.org/10.1038/s41418-018-0100-0