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Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis.

ABSTRACT: Gambogic acid (GA), a xanthonoid extracted from the resin of the tree, Garcinia hanburyi, was recently shown to exert anticancer activity in multiple studies, but the underlying action mechanism remains unclear. Here, we show that GA induces cancer cell death accompanied by vacuolation in vitro and in vivo. This GA-induced vacuolation in various cancer cells was derived from dilation of the endoplasmic reticulum (ER) and mitochondria, and was blocked by cycloheximide. These findings suggest that GA kills cancer cells by inducing paraptosis, a vacuolization-associated cell death. We found that megamitochondria formation, which arose from the fusion of swollen mitochondria, preceded the fusion of ER-derived vacuoles. GA-induced proteasomal inhibition was found to contribute to the ER dilation and ER stress seen in treated cancer cells, and megamitochondria formation was followed by mitochondrial membrane depolarization. Interestingly, GA-induced paraptosis was effectively blocked by various thiol-containing antioxidants, and this effect was independent of ROS generation. We observed that GA can react with cysteinyl thiol to form Michael adducts, suggesting that the ability of GA to covalently modify the nucleophilic cysteinyl groups of proteins may cause protein misfolding and subsequent accumulation of misfolded proteins within the ER and mitochondria. Collectively, our findings show that disruption of thiol proteostasis and subsequent paraptosis may critically contribute to the anti-cancer effects of GA.

SUBMITTER: Seo MJ

PROVIDER: S-EPMC6385239 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis.

Seo Min Ji MJ Lee Dong Min DM Kim In Young IY Lee Dongjoo D Choi Min-Koo MK Lee Joo-Youn JY Park Seok Soon SS Jeong Seong-Yun SY Choi Eun Kyung EK Choi Kyeong Sook KS

Cell death & disease 20190222 3

Gambogic acid (GA), a xanthonoid extracted from the resin of the tree, Garcinia hanburyi, was recently shown to exert anticancer activity in multiple studies, but the underlying action mechanism remains unclear. Here, we show that GA induces cancer cell death accompanied by vacuolation in vitro and in vivo. This GA-induced vacuolation in various cancer cells was derived from dilation of the endoplasmic reticulum (ER) and mitochondria, and was blocked by cycloheximide. These findings suggest that ...[more]

PMID: 30796201

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Project description:BackgroundAdiponectin, the most abundant adipokine derived from adipose tissue, exhibits a potent suppressive effect on the growth of breast cancer cells; however, the underlying molecular mechanisms for this effect are not completely understood. Fatty acid metabolic reprogramming has recently been recognized as a crucial driver of cancer progression. Adiponectin demonstrates a wide range of metabolic activities for the modulation of lipid metabolism under physiological conditions. However, the biological actions of adiponectin in cancer-specific lipid metabolism and its role in the regulation of cancer cell growth remain elusive.MethodsThe effects of adiponectin on fatty acid metabolism were evaluated by measuring the cellular neutral lipid pool, free fatty acid level, and fatty acid oxidation (FAO). Colocalization between fluorescent-labeled lipid droplets and LC3/lysosomes was employed to detect lipophagy activation. Cell viability and apoptosis were examined by MTS assay, caspase-3/7 activity measurement, TUNEL assay, and Annexin V binding assay. Gene expression was determined by real time-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The transcriptional activity of SREBP-1 was examined by a specific dsDNA binding assay. The modulatory roles of SIRT-1 and adiponectin-activated mediators were confirmed by gene silencing and/or using their pharmacological inhibitors. Observations from in vitro assays were further validated in an MDA-MB-231 orthotopic breast tumor model.ResultsGlobular adiponectin (gAcrp) prominently decreased the cellular lipid pool in different breast cancer cells. The cellular lipid deficiency promoted apoptosis by causing disruption of lipid rafts and blocking raft-associated signal transduction. Mechanistically, dysregulated cellular lipid homeostasis by adiponectin was induced by two concerted actions: 1) suppression of fatty acid synthesis (FAS) through downregulation of SREBP-1 and FAS-related enzymes, and 2) stimulation of lipophagy-mediated lipolysis and FAO. Notably, SIRT-1 induction critically contributed to the adiponectin-induced metabolic alterations. Finally, fatty acid metabolic remodeling by adiponectin and the key role of SIRT-1 were confirmed in nude mice bearing breast tumor xenografts.ConclusionThis study elucidates the multifaceted role of adiponectin in tumor fatty acid metabolic reprogramming and provides evidence for the connection between its metabolic actions and suppression of breast cancer.

Project description:Background Gastric cancer (GC) is a major cancer-related mortality disease. Gambogic acid (GA) has been investigated to inhibit cancer progression. In the present study, the molecular mechanism of GA in regulating GC progression was studied. Methods The expression levels of circular RNA ASAP2 (circ_ASAP2), miR-33a-5p and cyclin-dependent kinases 7 (CDK7) were detected by quantitative real-time polymerase reaction (qRT-PCR). CDK7 protein level was evaluated by Western blot. Cell colony formation assay, 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, transwell assay and flow cytometry analysis were employed to reveal the functional effects among circ_ASAP2, miR-33a-5p and CDK7 on GA-induced GC progression. Mechanistically, the binding relationship between miR-33a-5p and circ_ASAP2 or CDK7 was predicted with starBase v3.0 online database and verified by dual-luciferase reporter assay. In vivo tumor formation assay was used to explain the impacts of GA treatment on GC growth in vivo. Results Circ_ASAP2 and CDK7 expression were downregulated in GA-induced GC cells compared with GC cells. MiR-33a-5p expression was upregulated in GA-induced GC cells relative to GC cells. The protein expression level of CDK7 was lower in GA-induced GC cells than that in GC cells. Further, circ_ASAP2 overexpression decreased GA-induced inhibition effects on cell proliferation, migration and invasion and GA-induced promotion effect on cell apoptosis in both AGS and HGC-27 cells, whereas this phenomenon was reversed by miR-33a-5p. In addition, circ_ASAP2 functioned as a sponge of miR-33a-5p and miR-33a-5p was associated with CDK7. Furthermore, GA treatment inhibited GC growth in vivo. Conclusion Circ_ASAP2 overexpression promoted cell proliferation, migration and invasion, whereas inhibited cell apoptosis by upregulating CDK7 expression through binding to miR-33a-5p in GA-induced GC cells. This study provided a theoretical basis in GC treatment with GA.

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Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis.

Publications

Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis.

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