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
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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.
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.