Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells.
Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells.
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DOI：
10.1038/s41419-018-1083-y
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发表时间：
2018-10-15
影响因子：
9
通讯作者：
Lyu Y
中科院分区：
文献类型：
--
作者：
Chen L;Zhang J;Lyu Z;Chen Y;Ji X;Cao H;Jin M;Zhu J;Yang J;Ling R;Xing J;Ren T;Lyu Y
线粒体形态是通过连续的分裂和融合的动态循环来重塑的。新出现的数据表明，线粒体分裂和融合之间的平衡失调与几种类型的肿瘤的进展有关。然而，线粒体动力学的状态及其在乳腺癌，特别是在三阴性乳腺癌中的潜在生物学作用尚不完全清楚。在此，我们报道了与相应的瘤周组织相比，BC组织中线粒体分裂显著增加，尤其是在TNBC组织中。同时，我们的数据显示，Drp1在TNBC中上调，而Mfn1在TNBC中下调。此外，在TNBC患者中，线粒体分裂增加与较差的预后相关。线粒体分裂促进了TNBC细胞在体外和体内的存活。此外，我们在TNBC细胞中发现了线粒体分裂与Notch信号通路之间的正反馈回路，实验证据证明，Notch信号的激活促进了Drp1介导的线粒体分裂，而Drp1介导的线粒体分裂反过来又促进了Notch信号的激活，最终通过提高Survivin的表达水平促进了TNBC细胞的存活。抑制Notch1或Drp1会显著削弱另一种的激活，从而抑制TNBC细胞的存活和增殖。总之，我们的数据揭示了一种新的机制，即线粒体分裂和Notch信号之间的正反馈循环通过增加Survivin的表达来促进TNBC细胞的生存、增殖和凋亡抵抗，从而促进肿瘤的进展。
Mitochondrial morphology is remodeled by continuous dynamic cycles of fission and fusion. Emerging data have shown that the disturbance of balance between mitochondrial fission and fusion is involved in the progression of several types of neoplasms. However, the status of mitochondrial dynamics and its potential biological roles in breast cancer (BC), particularly in triple negative BC (TNBC) are not fully clear. Here, we reported that the mitochondrial fission was significantly increased in BC tissues, especially in the TNBC tissues, when compared with that in the corresponding peritumor tissues. Meanwhile, our data showed that Drp1 was upregulated, while Mfn1 was downregulated in TNBC. Moreover, elevated mitochondrial fission was associated with poorer prognosis in TNBC patients. Mitochondrial fission promoted the survival of TNBC cells both in vitro and in vivo. Furthermore, we identified a positive feedback loop between mitochondrial fission and Notch signaling pathway in TNBC cells, as proved by the experimental evidence that the activation of Notch signaling enhanced Drp1-mediated mitochondrial fission and Drp1-mediated mitochondrial fission in turn promoted the activation of Notch signaling, which ultimately promoted the cell survival of TNBC via increasing survivin expression level. Inhibition of either Notch1 or Drp1 significantly impaired the activation of the other, leading to the suppression of TNBC cell survival and proliferation. Collectively, our data reveal a novel mechanism that the positive feedback loop between mitochondrial fission and Notch signaling promotes the survival, proliferation and apoptotic resistance of TNBC cells via increasing survivin expression and thus favors cancer progression.
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DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
Notch-1信号传导促进人非小细胞肺癌细胞中生存素的表达
影响因子：
3.6
作者：
Chen, Yuqing;Li, Dianming;Wang, Xiaojing
通讯作者：
Wang, Xiaojing
影响因子：
--
作者：
Luk SU;Xue H;Cheng H;Lin D;Gout PW;Fazli L;Collins CC;Gleave ME;Wang Y
通讯作者：
Wang Y
DOI：
10.1186/bcr2200
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Lee CW;Simin K;Liu Q;Plescia J;Guha M;Khan A;Hsieh CC;Altieri DC
通讯作者：
Altieri DC
影响因子：
254.7
作者：
Mettlin, C
通讯作者：
Mettlin, C