Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer.
Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer.
复制标题
小分子 RL71 触发过度自噬细胞死亡，作为三阴性乳腺癌的潜在治疗策略。
DOI：
10.1038/cddis.2017.444
复制
发表时间：
2017-09-14
影响因子：
9
通讯作者：
Xu Q
中科院分区：
文献类型：
--
作者：
Gao J;Fan M;Peng S;Zhang M;Xiang G;Li X;Guo W;Sun Y;Wu X;Wu X;Liang G;Shen Y;Xu Q
三阴性乳腺癌（TNBC）具有侵袭性表型和不良预后，这是由于转移进展的高倾向和缺乏特异性靶向治疗。在这里，我们揭示了靶向肌浆网/内质网钙-ATP酶2（SERCA 2）的小分子RL 71对所有测试的TNBC细胞都表现出有效的抗癌活性。除了细胞凋亡诱导之外，RL 71触发过度的自噬细胞死亡，这是RL 71诱导的TNBC细胞死亡的主要贡献者。RL 71通过抑制SERCA 2活性，促进Ca 2+从内质网释放到胞浆中。钙稳态的破坏诱导内质网应激，导致细胞凋亡。更重要的是，升高的细胞内钙信号通过激活CaMKK-AMPK-mTOR通路和线粒体损伤诱导自噬。在两个TNBC异种移植小鼠模型中，RL 71也显示出强的功效，包括抑制肿瘤生长、减少转移以及延长存活时间。这些发现表明SERCA 2是TNBC治疗的先前未知的靶候选物，并支持自噬诱导剂可用作TNBC治疗中的新疗法的想法。
Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71-induced TNBC cell death. RL71 augmented the release of Ca 2+ from the endoplasmic reticulum (ER) into the cytosol by inhibiting SERCA2 activity. The disruption of calcium homeostasis induced ER stress, leading to apoptosis. More importantly, the elevated intracellular calcium signals induced autophagy through the activation of the CaMKK-AMPK-mTOR pathway and mitochondrial damage. In two TNBC xenograft mouse models, RL71 also displayed strong efficacy including the inhibition of tumor growth, the reduction of metastasis, as well as the prolongation of survival time. These findings suggest SERCA2 as a previous unknown target candidate for TNBC treatment and support the idea that autophagy inducers could be useful as new therapeutics in TNBC treatment.
登录
查看更多内容
影响因子：
0.6
作者：
Jangamreddy JR;Los MJ
通讯作者：
Los MJ
影响因子：
2.1
作者：
Santulli G;Totary-Jain H
通讯作者：
Totary-Jain H
影响因子：
3.3
作者：
Chang, Shu-Jyuan;Ou-Yang, Fu;Kwan, Aij-Lie
通讯作者：
Kwan, Aij-Lie
影响因子：
2.8
作者：
Christensen, S. Brogger;Skytte, Dorthe Mondrup;Isaacs, John T.
通讯作者：
Isaacs, John T.
Jaceosidin通过线粒体途径诱导人卵巢癌细胞凋亡。
影响因子：
--
作者：
Lv, Wen;Sheng, Xia;Chen, Ting;Xu, Qiang;Xie, Xing
通讯作者：
Xie, Xing