title: IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway.
abstract: 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.
authors.affiliation: Department of Pathology and Helen Diller Family Comprehensive Cancer Center; University of California, San Francisco; San Francisco, CA USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.forename: Jayanta
authors.initials: J
authors.lastname: Debnath
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039422:Integrin alpha3 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000906:Antibodies; D051550:I-kappa B Kinase; D039422:Integrin alpha3; D019012:Integrin beta1; D020930:MAP Kinase Kinase Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7
keywords: anoikis; autophagy; extracellular matrix; integrin; mammary epithelial cells