Modulation of Autophagy by Ursolic and Betulinic Acids: Distinct Cytotoxic and Membrane-Disruption in Malignant and Nonmalignant Cells.

IF 3.1 3区 生物学 Q3 CELL BIOLOGY
Waleska Kerllen Martins, Tayana Mazin Tsubone, Chimara Emilia Nascimento Sanches, Cleidiane de Sousa Rocha, Ricardo Scarparo Navarro, Beatriz Simonsen Stolf, Susana Nogueira Diniz, Rosangela Itri, Mauricio S Baptista
{"title":"Modulation of Autophagy by Ursolic and Betulinic Acids: Distinct Cytotoxic and Membrane-Disruption in Malignant and Nonmalignant Cells.","authors":"Waleska Kerllen Martins, Tayana Mazin Tsubone, Chimara Emilia Nascimento Sanches, Cleidiane de Sousa Rocha, Ricardo Scarparo Navarro, Beatriz Simonsen Stolf, Susana Nogueira Diniz, Rosangela Itri, Mauricio S Baptista","doi":"10.1002/cbin.70073","DOIUrl":null,"url":null,"abstract":"<p><p>Autophagy is a critical adaptive mechanism in tumor cells that promotes survival under stress, but when dysregulated, it may trigger programmed cell death. The pentacyclic triterpenoids betulinic acid (BA) and ursolic acid (UA) are structurally related compounds that modulate autophagy; however, comparative insights into their effects on nonmalignant and malignant cells, as well as model membranes, remain limited. Here, we investigated the distinct cellular outcomes induced by UA and BA in nonmalignant keratinocytes (HaCaT) and malignant cell lines (A549, HeLa, MCF7, MES-SA, PC3, SKMEL-25/28), as well as their interactions with mitochondrial membrane mimetics. At 20 μM, BA reduced HaCaT proliferation by 70%, while UA achieved only 30% inhibition. BA induced pronounced mitochondrial dysfunction (i.e., 60%), mitophagy activation, and autophagy-associated cell death linked to a lysosomal-mitochondrial stress axis. In contrast, UA induced lysosomal membrane permeabilization and the release of cathepsin B, resulting in ~50% cell death. In malignant cell lines, BA reduced viability to ~40%, whereas UA showed selective toxicity (53%-73% survival). Cotreatment with chloroquine enhanced UA's cytotoxicity by simulating BA-like lysosomal accumulation. Biophysical assays revealed differential membrane disruption profiles: BA permeabilized cardiolipin-rich membranes, while UA exerted milder surface-level effects. These findings illustrate how structurally similar triterpenoids exert divergent effects on cellular membranes, autophagic flux, and cell fate, offering a foundation for designing selective anticancer agents that target the lysosomal-mitochondrial axis.</p>","PeriodicalId":9806,"journal":{"name":"Cell Biology International","volume":" ","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Biology International","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1002/cbin.70073","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Autophagy is a critical adaptive mechanism in tumor cells that promotes survival under stress, but when dysregulated, it may trigger programmed cell death. The pentacyclic triterpenoids betulinic acid (BA) and ursolic acid (UA) are structurally related compounds that modulate autophagy; however, comparative insights into their effects on nonmalignant and malignant cells, as well as model membranes, remain limited. Here, we investigated the distinct cellular outcomes induced by UA and BA in nonmalignant keratinocytes (HaCaT) and malignant cell lines (A549, HeLa, MCF7, MES-SA, PC3, SKMEL-25/28), as well as their interactions with mitochondrial membrane mimetics. At 20 μM, BA reduced HaCaT proliferation by 70%, while UA achieved only 30% inhibition. BA induced pronounced mitochondrial dysfunction (i.e., 60%), mitophagy activation, and autophagy-associated cell death linked to a lysosomal-mitochondrial stress axis. In contrast, UA induced lysosomal membrane permeabilization and the release of cathepsin B, resulting in ~50% cell death. In malignant cell lines, BA reduced viability to ~40%, whereas UA showed selective toxicity (53%-73% survival). Cotreatment with chloroquine enhanced UA's cytotoxicity by simulating BA-like lysosomal accumulation. Biophysical assays revealed differential membrane disruption profiles: BA permeabilized cardiolipin-rich membranes, while UA exerted milder surface-level effects. These findings illustrate how structurally similar triterpenoids exert divergent effects on cellular membranes, autophagic flux, and cell fate, offering a foundation for designing selective anticancer agents that target the lysosomal-mitochondrial axis.

熊果酸和白桦酸对自噬的调节:恶性和非恶性细胞中不同的细胞毒性和膜破坏。
自噬是肿瘤细胞促进应激下存活的关键适应性机制,但当其失调时,可能引发程序性细胞死亡。五环三萜白桦酸(BA)和熊果酸(UA)是结构相关的调节自噬的化合物;然而,关于它们对非恶性和恶性细胞以及模型膜的影响的比较见解仍然有限。在这里,我们研究了UA和BA在非恶性角质形成细胞(HaCaT)和恶性细胞系(A549、HeLa、MCF7、MES-SA、PC3、SKMEL-25/28)中诱导的不同细胞结果,以及它们与线粒体膜模拟物的相互作用。在20 μM时,BA抑制HaCaT增殖70%,而UA仅抑制30%。BA诱导明显的线粒体功能障碍(即60%)、线粒体自噬激活以及与溶酶体-线粒体应激轴相关的自噬相关细胞死亡。相反,UA诱导溶酶体膜渗透和组织蛋白酶B的释放,导致约50%的细胞死亡。在恶性细胞系中,BA将生存能力降低至40%,而UA则表现出选择性毒性(53%-73%的存活率)。与氯喹共处理通过模拟ba样溶酶体积累增强UA的细胞毒性。生物物理分析揭示了不同的膜破坏特征:BA渗透了富含心磷脂的膜,而UA则发挥了较温和的表面作用。这些发现说明了结构相似的三萜如何对细胞膜、自噬通量和细胞命运产生不同的影响,为设计靶向溶酶体-线粒体轴的选择性抗癌药物提供了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Cell Biology International
Cell Biology International 生物-细胞生物学
CiteScore
7.60
自引率
0.00%
发文量
208
审稿时长
1 months
期刊介绍: Each month, the journal publishes easy-to-assimilate, up-to-the minute reports of experimental findings by researchers using a wide range of the latest techniques. Promoting the aims of cell biologists worldwide, papers reporting on structure and function - especially where they relate to the physiology of the whole cell - are strongly encouraged. Molecular biology is welcome, as long as articles report findings that are seen in the wider context of cell biology. In covering all areas of the cell, the journal is both appealing and accessible to a broad audience. Authors whose papers do not appeal to cell biologists in general because their topic is too specialized (e.g. infectious microbes, protozoology) are recommended to send them to more relevant journals. Papers reporting whole animal studies or work more suited to a medical journal, e.g. histopathological studies or clinical immunology, are unlikely to be accepted, unless they are fully focused on some important cellular aspect. These last remarks extend particularly to papers on cancer. Unless firmly based on some deeper cellular or molecular biological principle, papers that are highly specialized in this field, with limited appeal to cell biologists at large, should be directed towards journals devoted to cancer, there being very many from which to choose.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信