PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy.
PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy.
复制标题
PrLZ 通过抑制 LKB1/AMPK 介导的自噬增加前列腺癌多西紫杉醇耐药性
作者：
Zeng J;Liu W;Fan YZ;He DL;Li L
基本原理：多西他赛介导的化疗是一线标准方法，已确定对转移性去势抵抗性前列腺癌（mCRPC）患者具有生存优势。然而，相当大比例的患者最终由于耐药性而变得难治。具体机制尚不清楚。我们以前曾报道，前列腺亮氨酸拉链（PrLZ），前列腺癌（PCa）的一个特定的癌基因，促进PCa细胞生长在去势抵抗阶段，从而表明PrLZ在CRPC的进展至关重要的作用。本研究旨在探讨PrLZ在PCa多西他赛耐药中的作用，重点关注PrLZ调控的自噬途径。研究方法：将人PCa PC 3、LNCaP和C4-2细胞系用作体外模型系统，将PCa异种移植物和PrLZ敲除小鼠用作体内模型系统。MTT法和流式细胞术检测多西紫杉醇诱导PCa细胞凋亡和死亡。采用免疫印迹、免疫沉淀、siRNA沉默和质粒过表达等方法分析PrLZ对自噬和肝激酶B1/AMP活化蛋白激酶（LKB 1/AMPK）信号通路的调节作用。结果：PrLZ在体内外均能增加紫杉醇介导的耐药。机械解剖显示PrLZ与LKB 1相互作用，进一步抑制LKB 1/AMPK信号的激活，从而对自噬的诱导产生负面影响。此外，PrLZ/LKB 1介导的自噬在体外和体内均对紫杉醇诱导的细胞死亡和凋亡产生抗性。结论：这些发现确定了PrLZ在自噬操纵中的新作用，并为PCa中的多西他赛化疗耐药性提供了新的见解，表明了通过靶向这种新发现的信号通路治疗mCRPC的新策略。
Rationale: Docetaxel-mediated chemotherapy is the first-line standard approach and has been determined to show a survival advantage for metastatic castration-resistant prostate cancer (mCRPC) patients. However, a substantial proportion of patients eventually becomes refractory due to drug resistance. The detailed mechanisms remain unclear. We have previously reported that Prostate Leucine Zipper (PrLZ), a specific oncogene of prostate cancer (PCa), promotes PCa cell growth at the castration-resistant stage, thus suggesting a vital role of PrLZ in the progression of CRPC. In this study, we aimed to investigate the role of PrLZ in docetaxel resistance in PCa, focusing on PrLZ-regulating autophagy pathway. Methods: Human PCa PC3, LNCaP and C4-2 cell lines were used as the model system in vitro and PCa xenografts and PrLZ-knockout mice were used as the model system in vivo. Docetaxel-induced cell death and apoptosis in PCa were determined by MTT and flow cytometry assay. The role of PrLZ on the regulation of autophagy and liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway was analyzed using immunoblotting, immunoprecipitation, siRNA silencing and plasmid overexpression. Results: PrLZ increased docetaxel-mediated drug resistance both in vitro and in vivo. Mechanistic dissection revealed that PrLZ interacted with LKB1 and further inhibited the activation of LKB1/AMPK signals, which negatively contributed to the induction of autophagy. Moreover, PrLZ/LKB1-mediated autophagy conferred resistance to docetaxel-induced cell death and apoptosis both in vitro and in vivo. Conclusion: These findings identify a novel role of PrLZ in autophagy manipulation and provide new insight into docetaxel chemoresistance in PCa, suggesting a new strategy for treating mCRPC by targeting this newly identified signaling pathway.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
4.9
作者：
Hwang C
通讯作者：
Hwang C
DOI：
10.1073/pnas.1615455113
发表时间：
2016-11-22
影响因子：
11.1
作者：
Cohen-Kaplan, Victoria;Livneh, Ido;Ciechanover, Aaron
通讯作者：
Ciechanover, Aaron
影响因子：
50.3
作者：
Domingo-Domenech J;Vidal SJ;Rodriguez-Bravo V;Castillo-Martin M;Quinn SA;Rodriguez-Barrueco R;Bonal DM;Charytonowicz E;Gladoun N;de la Iglesia-Vicente J;Petrylak DP;Benson MC;Silva JM;Cordon-Cardo C
通讯作者：
Cordon-Cardo C
影响因子：
64.8
作者：
Kuma, A;Hatano, M;Mizushima, N
通讯作者：
Mizushima, N