Microtubule acetylation and PERK activation facilitate eribulin-induced mitochondrial calcium accumulation and cell death.

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Seongeun Song, Panseon Ko, Seula Keum, Jangho Jeong, Ye Eun Hwang, Minwoo Lee, Jee-Hye Choi, Youn-Sang Jung, Sung Hyun Kim, Sangmyung Rhee
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Abstract

Over the past few decades, microtubules have been targeted by various anticancer drugs, including paclitaxel and eribulin. Despite their promising effects, the development of drug resistance remains a challenge. We aimed to define a novel cell death mechanism that targets microtubules using eribulin and to assess its potential in overcoming eribulin resistance. Notably, treating non-resistant breast cancer cells with eribulin led to increased microtubule acetylation around the nucleus and cell death. Conversely, eribulin-resistant (EriR) cells did not exhibit a similar increase in acetylation, even at half-maximal inhibitory concentrations. Interestingly, silencing the ATAT1 gene, which encodes the α-tubulin N-acetyltransferase 1 (the enzyme responsible for microtubule acetylation), induces eribulin resistance, mirroring the phenotype of EriR cells. Moreover, eribulin-induced acetylation of microtubules facilitates the transport of Ca2+ from the ER to the mitochondria, releasing cytochrome c and subsequent cell death. Transcriptome analysis of EriR cells revealed a significant downregulation of ER stress-induced apoptotic signals, particularly the activity of protein kinase RNA-like ER kinase (PERK), within the unfolded protein response signaling system. Pharmacological induction of microtubule acetylation through a histone deacetylase 6 inhibitor combined with the activation of PERK signaling using the PERK activator CCT020312 in EriR cells enhanced mitochondrial Ca2+ accumulation and subsequent cell death. These findings reveal a novel mechanism by which eribulin-induced microtubule acetylation and increased PERK activity lead to Ca2+ overload from the ER to the mitochondria, ultimately triggering cell death. This study offers new insights into strategies for overcoming resistance to microtubule-targeting agents.

微管乙酰化和PERK激活促进埃瑞布林诱导的线粒体钙积累和细胞死亡。
在过去的几十年里,微管已经成为各种抗癌药物的靶点,包括紫杉醇和艾瑞布林。尽管它们有很好的效果,但耐药性的发展仍然是一个挑战。我们的目的是定义一个新的细胞死亡机制,针对微管使用艾瑞布林,并评估其克服艾瑞布林耐药的潜力。值得注意的是,用伊瑞布林治疗非耐药乳腺癌细胞导致细胞核周围微管乙酰化增加和细胞死亡。相反,耐布林(EriR)细胞没有表现出类似的乙酰化增加,即使在最大抑制浓度的一半。有趣的是,沉默编码α-微管蛋白n -乙酰转移酶1(负责微管乙酰化的酶)的ATAT1基因,可诱导eribulin抗性,反映EriR细胞的表型。此外,艾瑞布林诱导的微管乙酰化促进Ca2+从内质网转运到线粒体,释放细胞色素c和随后的细胞死亡。EriR细胞的转录组分析显示,内质网应激诱导的凋亡信号显著下调,特别是未折叠蛋白反应信号系统中蛋白激酶rna样内质网激酶(PERK)的活性。通过组蛋白去乙酰化酶6抑制剂联合PERK激活剂CCT020312在EriR细胞中诱导微管乙酰化,增强线粒体Ca2+积累和随后的细胞死亡。这些发现揭示了一种新的机制,通过这种机制,埃布林诱导的微管乙酰化和PERK活性的增加导致内质网到线粒体的Ca2+过载,最终引发细胞死亡。这项研究为克服对微管靶向药物的耐药性提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cellular and Molecular Life Sciences
Cellular and Molecular Life Sciences 生物-生化与分子生物学
CiteScore
13.20
自引率
1.20%
发文量
546
审稿时长
1.0 months
期刊介绍: Journal Name: Cellular and Molecular Life Sciences (CMLS) Location: Basel, Switzerland Focus: Multidisciplinary journal Publishes research articles, reviews, multi-author reviews, and visions & reflections articles Coverage: Latest aspects of biological and biomedical research Areas include: Biochemistry and molecular biology Cell biology Molecular and cellular aspects of biomedicine Neuroscience Pharmacology Immunology Additional Features: Welcomes comments on any article published in CMLS Accepts suggestions for topics to be covered
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