{"title":"Microtubule acetylation and PERK activation facilitate eribulin-induced mitochondrial calcium accumulation and cell death.","authors":"Seongeun Song, Panseon Ko, Seula Keum, Jangho Jeong, Ye Eun Hwang, Minwoo Lee, Jee-Hye Choi, Youn-Sang Jung, Sung Hyun Kim, Sangmyung Rhee","doi":"10.1007/s00018-024-05565-w","DOIUrl":null,"url":null,"abstract":"<p><p>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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> accumulation and subsequent cell death. These findings reveal a novel mechanism by which eribulin-induced microtubule acetylation and increased PERK activity lead to Ca<sup>2+</sup> 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.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"32"},"PeriodicalIF":6.2000,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11688268/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular and Molecular Life Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s00018-024-05565-w","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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