AMPK/GSK3β/β-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming
AMPK/GSK3β/β-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming
复制标题
AMPK/GSK3β/β-连环蛋白级联触发的 CEMIP 过度表达通过增强代谢重编程促进失巢凋亡抵抗性前列腺癌细胞的迁移和侵袭
DOI：
10.1096/fj.201701078r
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发表时间：
2018-07-01
期刊：
影响因子：
4.8
通讯作者：
Xing, Yifei
中科院分区：
文献类型：
--
作者：
Zhang, Peng;Song, Yarong;Xing, Yifei
前列腺癌（PCa）是最常见的实体肿瘤之一，转移是成年男性死亡的第二大原因。Anoikis是一种程序性细胞死亡，是由细胞脱离细胞外基质（ECM）引起的，它是锚定非依赖性细胞生长和转移形成的关键保护机制。然而，在没有ECM附着的情况下，代谢模式的改变和对anoikis的耐受性促进了循环系统中侵袭性癌细胞的存活及其向远处转移。迄今为止，在前列腺癌中很少有分子靶点被报道同时阻止anoikis的耐药、代谢重编程和转移。在本研究中，在抗抑郁PCa细胞中发现了迁移、侵袭、丙酮酸生成、乳酸生成、ATP水平升高以及脱落诱导的细胞凋亡受损，基因组微阵列分析表明细胞迁移诱导蛋白（CEMIP）是调控上述恶性行为的潜在分子靶点。进一步的研究表明，AMPK/糖原合成酶激酶3 (GSK3)/-catenin级联触发的CEMIP在抗抑郁PCa细胞中的过表达可能与局部进展、代谢转移、细胞迁移和侵袭有关。然而，通过聚集规律间隔短回文重复序列(CRISPR)/CRISPR相关蛋白9在抗抑郁PCa细胞中敲除CEMIP，通过降低基质金属蛋白酶2 （MMP2）、VEGF、丙酮酸脱氢酶激酶异型4 （PDK4）和乳酸脱氢酶a的表达，逆转了所描述的生物效应。通过cemip介导的PDK4下调抑制糖酵解，通过降低MMP2和VEGF的表达，损害了抗酒精性PCa细胞的迁移和侵袭。我们的研究结果表明，AMPK/GSK3/-catenin级联触发的CEMIP过表达可能通过增强pdk4相关的代谢重编程来促进嗜酸性PCa细胞的迁移和侵袭，这可能为晚期PCa的治疗提供一个新的、有希望的治疗靶点。张鹏，宋艳，孙艳，李晓燕，陈丽，杨丽，邢艳，AMPK/GSK3/-catenin级联触发的CEMIP过表达通过增强代谢重编程促进抗激素前列腺癌细胞的迁移和侵袭。
Prostate cancer (PCa) represents one of the most common solid neoplasms, and metastasis is the second leading cause of death in adult males. Anoikis is a programmed cell death that is induced upon cell detachment from the extracellular matrix (ECM), which behaves as a critical protective mechanism for anchorage-independent cell growth and metastasis formation. However, in the absence of ECM attachment, shift of metabolic pattern and tolerance to anoikis facilitate the survival of aggressive cancer cells in the circulatory system as well as their metastasis to distant sites. Few molecular targets in PCa have thus far been reported to prevent anoikis resistance, metabolic reprogramming, and metastasis simultaneously. In the present study, elevated migration, invasion, pyruvate production, lactate generation, ATP level, and impaired detachment-induced apoptosis were found in anoikis-resistant PCa cells, and genome microarray analysis demonstrated that the cell migration-inducing protein (CEMIP) was a potential molecular target for the regulation of the aforementioned malignant behaviors. Additional investigation revealed that the AMPK/glycogen synthase kinase 3 (GSK3)/-catenin cascade-triggered CEMIP overexpression in anoikis-resistant PCa cells might be implicated in local progression, metabolic shift, and cellular migration and invasion, whereas knockout of CEMIP by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 in anoikis-resistant PCa cells reversed the described bioeffects by reducing expressions of matrix metalloproteinase 2 (MMP2), VEGF, pyruvate dehydrogenase kinase isoform 4 (PDK4), and lactate dehydrogenase A. In addition, inhibition of glycolysis by CEMIP-mediated PDK4 down-regulation impaired the migration and invasion of anoikis-resistant PCa cells by attenuating MMP2 and VEGF expressions. Our findings establish that AMPK/GSK3/-catenin cascade-triggered CEMIP overexpression might promote migration and invasion in anoikis-resistant PCa cells by enhancing PDK4-associated metabolic reprogramming, which may provide a novel, promising therapeutic target for the treatment of advanced PCa.Zhang, P., Song, Y., Sun, Y., Li, X., Chen, L., Yang, L., Xing, Y. AMPK/GSK3/-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming.