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IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway
| Content Provider | Scilit |
|---|---|
| Author | Chen, Nan Debnath, Jayanta |
| Copyright Year | 2013 |
| Description | Adherent cells require proper integrin-mediated extracellular matrix (ECM) engagement for growth and survival; normal cells deprived of proper ECM contact undergo anoikis. At the same time, autophagy is induced as a survival pathway in both fibroblasts and epithelial cells upon ECM detachment. Here, we further define the intracellular signals that mediate detachment-induced autophagy and uncover an important role for the IκB kinase (IKK) complex in the induction of autophagy in mammary epithelial cells (MECs) deprived of ECM contact. Whereas the PI3K-AKT-MTORC1 pathway activation potently inhibits autophagy in ECM-detached fibroblasts, enforced activation of this pathway is not sufficient to suppress detachment-induced autophagy in MECs. Instead, inhibition of IKK, as well as its upstream regulator, MAP3K7/TAK1, significantly attenuates detachment-induced autophagy in MECs. Furthermore, function-blocking experiments corroborate that both IKK activation and autophagy induction result from decreased ITGA3-ITGB1 (α3β1 integrin) function. Finally, we demonstrate that pharmacological IKK inhibition enhances anoikis and accelerates luminal apoptosis during acinar morphogenesis in three-dimensional culture. Based on these results, we propose that the IKK complex functions as a key mediator of detachment-induced autophagy and anoikis resistance in epithelial cells. |
| Related Links | https://www.tandfonline.com/doi/pdf/10.4161/auto.24870?needAccess=true https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748193/pdf https://www.landesbioscience.com/journals/autophagy/2012AUTO0661R3.pdf |
| Ending Page | 1227 |
| Page Count | 14 |
| Starting Page | 1214 |
| ISSN | 15548627 |
| e-ISSN | 15548635 |
| DOI | 10.4161/auto.24870 |
| Journal | Autophagy |
| Issue Number | 8 |
| Volume Number | 9 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2013-08-14 |
| Access Restriction | Open |
| Subject Keyword | Journal: Autophagy Biochemistry and Molecular Biology Anoikis Autophagy Extracellular Matrix Integrin Mammary Epithelial Cells |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Molecular Biology |
