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.

Vitamin B12b Enhances the Cytotoxicity of Diethyldithiocarbamate in a Synergistic Manner, Inducing the Paraptosis-Like Death of Human Larynx Carcinoma Cells

“…We did not reveal the formation of vacuoles from mitochondria, which often occurs in the paraptosis-like cell death [56]. It has been found in some studies that, on induction of paraptosis, mitochondria can retain high functional activity [57]. This feature was also characteristic of cells incubated with DDC + B 12b ; even at the stage of the formation of large vacuoles, we did not observe a decrease in the mitochondrial potential, Ca 2+ retention capacity, and ATP synthesis.…”

<p>Endocytosis and Organelle Targeting of Nanomedicines in Cancer Therapy</p>

“…Dilation of ER and ER stress are reported to result in paraptosis, a vacuolization-associated cell death in cancer cells. 143 Paraptosis can be induced by gambogic acid, an anticancer drug with xanthone structure, which makes ER a potential therapeutic target.…”

Iodine‑125 seed radiation induces ROS‑mediated apoptosis, autophagy and paraptosis in human esophageal squamous cell carcinoma cells

“…Paraptosis differs from necrosis in that, paraptosis does not result in early plasma membrane rupture and the release of cellular contents (21,22). Recent studies have shown that paraptosis-associated cell death is an important anti-cancer mechanism of various natural products, and is a novel area of interest in cancer research (23)(24)(25)(26). It has been reported that photodynamic therapy may also induce paraptosis (27); however, aside from one report on colorectal cancer (16), radiation has not hitherto been associated with paraptosis.…”