Intrinsic cellular signaling mechanisms determine the sensitivity of cancer cells to virus-induced apoptosis.
Intrinsic cellular signaling mechanisms determine the sensitivity of cancer cells to virus-induced apoptosis.
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内在的细胞信号传导机制决定癌细胞对病毒诱导的细胞凋亡的敏感性
DOI：
10.1038/srep37213
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发表时间：
2016-11-16
影响因子：
4.6
通讯作者：
Liao D
中科院分区：
文献类型：
--
作者：
Wang Y;Li D;Luo J;Tian G;Zhao LY;Liao D
上皮和间充质表型的癌细胞对凋亡刺激表现出不同的敏感性，但这种现象背后的机制仍然部分理解。我们构建了一种新的表达Ad 12 E1 A的重组腺病毒（Ad-E1 A12），它可以强烈地诱导细胞凋亡。Ad-E1 A12感染的上皮癌细胞表现出戏剧性的脱离和凋亡，而具有转移倾向的间充质表型的癌细胞对这种病毒的抵抗力明显更强。值得注意的是，上皮细胞的强制脱落并没有进一步使它们对Ad-E1 A12诱导的细胞凋亡敏感，这表明细胞脱落是Ad-E1 A12诱导的细胞凋亡的结果而不是原因。Ad-E1 A12通过独立的机制在不同的细胞类型中增加AKT 1和核糖体蛋白S6的磷酸化。Ad-E1 A12诱导的AKT 1磷酸化在上皮癌细胞中是PI 3 K依赖性的，在间充质癌细胞中是mTOR依赖性的。由于AKT 1降解，Ad-E1 A12诱导的脱落后的上皮癌细胞不能维持AKT活化，但在间充质癌细胞中维持AKT 1活化。上皮细胞限制性miR-200家族在间充质细胞中的表达限制了mTOR信号传导，并使其对Ad-E1 A12诱导的细胞杀伤敏感。因此，上皮癌细胞依赖于经典的PI 3 K-AKT信号传导途径来存活，而间充质癌细胞响应于强死亡刺激而部署PI 3 K非依赖性mT 0 RC 2-AKT轴。
Cancer cells of epithelial and mesenchymal phenotypes exhibit different sensitivities to apoptosis stimuli, but the mechanisms underlying this phenomenon remain partly understood. We constructed a novel recombinant adenovirus expressing Ad12 E1A (Ad-E1A12) that can strongly induce apoptosis. Ad-E1A12 infection of epithelial cancer cells displayed dramatic detachment and apoptosis, whereas cancer cells of mesenchymal phenotypes with metastatic propensity were markedly more resistant to this virus. Notably, forced detachment of epithelial cells did not further sensitize them to Ad-E1A12-induced apoptosis, suggesting that cell detachment is a consequence rather than the cause of Ad-E1A12-induced apoptosis. Ad-E1A12 increased phosphorylation of AKT1 and ribosomal protein S6 through independent mechanisms in different cell types. Ad-E1A12–induced AKT1 phosphorylation was PI3K-dependent in epithelial cancer cells, and mTOR-dependent in mesenchymal cancer cells. Epithelial cancer cells upon Ad-E1A12-induced detachment could not sustain AKT activation due to AKT1 degradation, but AKT1 activation was maintained in mesenchymal cancer cells. Expression of epithelial cell-restricted miR-200 family in mesenchymal cells limited mTOR signaling and sensitized them to Ad-E1A12-induced cell killing. Thus, epithelial cancer cells rely on the canonical PI3K-AKT signaling pathway for survival, while mesenchymal cancer cells deploy the PI3K-independent mTORC2-AKT axis in response to strong death stimuli.
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影响因子：
2.5
作者：
Howe EN;Cochrane DR;Richer JK
通讯作者：
Richer JK
影响因子：
7.8
作者：
Frisch, S M
通讯作者：
Frisch, S M
影响因子：
3.7
作者：
Howe EN;Cochrane DR;Cittelly DM;Richer JK
通讯作者：
Richer JK
影响因子：
29
作者：
Lamming DW;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
8
作者：
Grooteclaes, ML;Frisch, SM
通讯作者：
Frisch, SM