Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer
Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer
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DOI：
10.1038/s41598-019-44346-5
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发表时间：
2019-05-24
影响因子：
4.6
通讯作者：
Gleave, Martin E.
中科院分区：
文献类型：
--
作者：
Kretschmer, Alexander;Zhang, Fan;Gleave, Martin E.
Tunneling nanotubes（TNTs）是一种基于肌动蛋白的膜状结构，用于细胞间通讯。我们定义了TNTs在前列腺癌（PCa）的压力适应和治疗抵抗中的作用。雄激素受体（AR）阻断和代谢应激诱导TNT，但不是在正常前列腺上皮或成骨细胞。共培养试验揭示了应激和非应激PCa细胞之间以及从应激PCa到成骨细胞的增强的TNT形成。应激诱导的分子伴侣clusterin和YB-1定位于TNT内，通过TNT双向转运，并以PI 3 K/AKT和Eps 8依赖的方式促进TNT的形成。由AR拮抗作用诱导以介导对AR途径抑制的抗性的AR变体也增强TNT产生并挽救簇蛋白或YB-1抑制的TNT形成的损失。TNT破坏使PCa对处理诱导的细胞死亡敏感。这些数据定义了一个机制网络，涉及应激诱导的伴侣蛋白和AR变体，PI 3 K/AKT信号，肌动蛋白重塑和TNT介导的细胞间通讯，赋予应激适应性细胞存活。
Tunneling nanotubes (TNTs) are actin-based membranous structures bridging distant cells for intercellular communication. We define roles for TNTs in stress adaptation and treatment resistance in prostate cancer (PCa). Androgen receptor (AR) blockade and metabolic stress induce TNTs, but not in normal prostatic epithelial or osteoblast cells. Co-culture assays reveal enhanced TNT formation between stressed and unstressed PCa cells as well as from stressed PCa to osteoblasts. Stress-induced chaperones clusterin and YB-1 localize within TNTs, are transported bi-directionally via TNTs and facilitate TNT formation in PI3K/AKT and Eps8-dependent manner. AR variants, induced by AR antagonism to mediate resistance to AR pathway inhibition, also enhance TNT production and rescue loss of clusterin- orYB-1-repressed TNT formation. TNT disruption sensitizes PCa to treatment-induced cell death. These data define a mechanistic network involving stress induction of chaperone and AR variants, PI3K/AKT signaling, actin remodeling and TNT-mediated intercellular communication that confer stress adaptative cell survival.