Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity.
Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity.
复制标题
通过激动 TR3 和减弱 Akt2 活性诱导癌细胞自噬死亡。
DOI：
10.1016/j.chembiol.2015.06.023
复制
发表时间：
2015
影响因子：
--
通讯作者：
Wu Qiao
中科院分区：
文献类型：
--
作者：
Wang Wei-jia;Wang Yuan;Hou Pei-pei;Li Feng-wei;Zhou Bo;Chen Hang-zi;Bian Xue-li;Cai Qi-xu;Xing Yong-zhen;He Jian-ping;Zhang Hongkui;Huang Pei-qiang;Lin Tianwei;Wu Qiao
凋亡抗性正成为癌症治疗的重要障碍，因为大多数治疗采用凋亡诱导途径。因此，寻找一种新的诱导癌细胞死亡的方法具有重要意义.我们先前报道了由核受体TR 3介导并由化学激动剂1-（3，4，5-三羟基苯基）壬-1-酮（THPN）驱动的自噬性细胞死亡在黑色素瘤的治疗中是非常有效的，但对任何其他癌症类型都不是。在这里，我们发现癌细胞对THPN的不敏感性源于高细胞Akt 2活性。Akt 2磷酸化干扰TR 3输出到细胞质并靶向线粒体，这导致自噬诱导。因此，TR 3介导的自噬可以通过下调Akt 2活性在其他不敏感的细胞中有效地诱导。通过对THPN结构的优化，开发出高效的抗肿瘤化合物。这项研究暗示了通过诱导自噬细胞死亡来治疗癌症的一般策略。
Apoptotic resistance is becoming a significant obstacle for cancer therapy as the majority of treatment takes the route of apoptotic induction. It is of great importance to develop an alternative strategy to induce cancer cell death. We previously reported that autophagic cell death mediated by nuclear receptor TR3 and driven by a chemical agonist, 1-(3,4,5-trihydroxyphenyl)nonan-1-one (THPN), is highly effective in the therapy of melanoma but not any other cancer types. Here, we discovered that the insensitivity of cancer cells to THPN originated from a high cellular Akt2 activity. Akt2 phosphorylation interferes with TR3 export to cytoplasm and targeting to mitochondria, which lead to the autophagic induction. Therefore, the TR3-mediated autophagy could be effectively induced in the otherwise insensitive cells by downregulating Akt2 activity. Highly effective antineoplastic compounds are developed through optimizing the structure of THPN. This study implicates a general strategy for cancer therapy by the induction of autophagic cell death.