Loss of anchorage primarily induces non-apoptotic cell death in a human mammary epithelial cell line under atypical focal adhesion kinase signaling.
Loss of anchorage primarily induces non-apoptotic cell death in a human mammary epithelial cell line under atypical focal adhesion kinase signaling.
复制标题
锚固的丧失主要诱导非典型局灶性粘附激酶信号下人类乳腺上皮细胞系中的非凋亡细胞死亡。
DOI：
10.1038/cddis.2014.583
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发表时间：
2015-01-22
影响因子：
9
通讯作者：
Shibanuma M
中科院分区：
文献类型：
--
作者：
Ishikawa F;Ushida K;Mori K;Shibanuma M
细胞生长和存活的锚定依赖性阻止了细胞在异位环境中不适当的生长或存活，并成为癌细胞转移的潜在障碍。因此，更好地了解正常细胞中的锚定依赖性反应是了解和阻碍癌细胞生长和存活的锚定独立性，并最终在转移过程中根除癌细胞的第一步。失巢凋亡是由于缺乏适当的细胞-细胞外基质黏附而导致的一种细胞凋亡，已被确定为正常上皮细胞对锚定丧失的主要反应。例如，在分离条件下，具有肌上皮特征的未转化乳腺上皮细胞系MCF-10A经历了依赖经典ERK信号转导的失巢凋亡。另一方面，最近的研究揭示了导致细胞死亡的各种表型，如自噬、坏死和角化，在分离的上皮细胞中不同于失巢凋亡。在本研究中，我们研究了hTERT永生化的原代人微血管内皮细胞(TertHMECs)中分离诱导的细胞死亡(DICD)，这种细胞是具有向腔细胞分化表型的双能祖细胞样细胞。与MCF-10A细胞相比，分离的TertHMECs没有观察到细胞凋亡；相反，随着粘着斑激酶(FAK)信号的下调，观察到以突起、角化和坏死为特征的非凋亡性细胞死亡。细胞死亡可以被FAK的锚定非依赖性活性克服，但不能被PI3K/AKT、SRC和MEK/ERK克服，这表明非典型的FAK信号通路在调控非凋亡性细胞死亡中起着关键作用。进一步分析发现，TRAIL(肿瘤坏死因子相关的凋亡诱导配体)作为FAK信号的中介体，在牙槽骨坏死的调控中起着重要作用，而p38MAPK在诱导坏死中起着重要作用。总体而言，本研究强调了在人微血管内皮细胞失去锚定时诱导的细胞死亡表型中突出的细胞亚型或分化阶段特异性。
Anchorage dependence of cellular growth and survival prevents inappropriate cell growth or survival in ectopic environments, and serves as a potential barrier to metastasis of cancer cells. Therefore, obtaining a better understanding of anchorage-dependent responses in normal cells is the first step to understand and impede anchorage independence of growth and survival in cancer cells and finally to eradicate cancer cells during metastasis. Anoikis, a type of apoptosis specifically induced by lack of appropriate cell-extracellular matrix adhesion, has been established as the dominant response of normal epithelial cells to anchorage loss. For example, under detached conditions, the untransformed mammary epithelial cell (MEC) line MCF-10 A, which exhibits myoepithelial characteristics, underwent anoikis dependent on classical ERK signaling. On the other hand, recent studies have revealed a variety of phenotypes resulting in cell death modalities distinct from anoikis, such as autophagy, necrosis, and cornification, in detached epithelial cells. In the present study, we characterized detachment-induced cell death (DICD) in primary human MECs immortalized with hTERT (TertHMECs), which are bipotent progenitor-like cells with a differentiating phenotype to luminal cells. In contrast to MCF-10 A cells, apoptosis was not observed in detached TertHMECs; instead, non-apoptotic cell death marked by features of entosis, cornification, and necrosis was observed along with downregulation of focal adhesion kinase (FAK) signaling. Cell death was overcome by anchorage-independent activities of FAK but not PI3K/AKT, SRC, and MEK/ERK, suggesting critical roles of atypical FAK signaling pathways in the regulation of non-apoptotic cell death. Further analysis revealed an important role of TRAIL (tumor necrosis factor (TNF)-related apoptosis-inducing ligand) as a mediator of FAK signaling in regulation of entosis and necrosis and a role of p38 MAPK in the induction of necrosis. Overall, the present study highlighted outstanding cell subtype or differentiation stage specificity in cell death phenotypes induced upon anchorage loss in human MECs.