IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway
IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway
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DOI：
10.4161/auto.24870
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发表时间：
2013-08-01
期刊：
影响因子：
13.3
通讯作者：
Debnath, Jayanta
中科院分区：
文献类型：
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作者：
Chen, Nan;Debnath, Jayanta
贴壁细胞需要适当的整合素介导的细胞外基质（ECM）参与生长和存活;正常细胞剥夺适当的ECM接触经历失巢凋亡。同时，在ECM脱离后，自噬作为成纤维细胞和上皮细胞中的存活途径被诱导。在这里，我们进一步定义了细胞内信号，介导细胞外基质诱导的自噬，并揭示了一个重要的作用，I κ B激酶（IKK）复合物在诱导自噬的乳腺上皮细胞（MEC）剥夺ECM接触。尽管PI 3 K-AKT-MTORC 1通路激活有效地抑制ECM分离的成纤维细胞中的自噬，但该通路的强制激活不足以抑制MEC中的自噬诱导的自噬。相反，IKK及其上游调节因子MAP 3 K7/TAK 1的抑制显著减弱了MEC中抑制诱导的自噬。此外，功能阻断实验证实IKK激活和自噬诱导均由ITGA 3-ITGB 1（α 3 β 1整联蛋白）功能降低引起。最后，我们证明，药理IKK抑制增强失巢凋亡和加速管腔细胞凋亡腺泡形态发生在三维培养。基于这些结果，我们提出IKK复合物的功能作为一个关键的调解人的炎症诱导的自噬和失巢凋亡的阻力上皮细胞。
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 I kappa B 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 (alpha 3 beta 1 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.