The natural anticancer agent cantharidin alters GPI-anchored protein sorting by targeting Cdc1-mediated remodeling in endoplasmic reticulum

Abstract

Edited by Ursula Jakob Cantharidin (CTD) is a potent anticancer small molecule produced by several species of blister beetle. It has been a traditional medicine for the management of warts and tumors for many decades. CTD suppresses tumor growth by inducing apoptosis, cell cycle arrest, and DNA damage and inhibits protein phosphatase 2 phosphatase activator (PP2A) and protein phosphatase 1 (PP1). CTD also alters lipid homeostasis, cell wall integrity, endocytosis, adhesion, and invasion in yeast cells. In this study, we identified additional molecular targets of CTD using a Saccharomyces cerevisiae strain that expresses a cantharidin resistance gene (CRG1), encoding a SAM-dependent methyltransferase that methylates and inactivates CTD. We found that CTD specifically affects phosphatidylethanolamine (PE)-associated functions that can be rescued by supplementing the growth media with ethanolamine (ETA). CTD also perturbed endoplasmic reticulum (ER) homeostasis and cell wall integrity by altering the sorting of glycosylphosphatidylinositol (GPI)-anchored proteins. A CTD-dependent genetic interaction profile of CRG1 revealed that the activity of the lipid phosphatase cell division control protein 1 (Cdc1) in GPI-anchor remodeling is the key target of CTD, independently of PP2A and PP1 activities. Moreover, experiments with human cells further suggested that CTD functions through a conserved mechanism in higher eukaryotes. Altogether, we conclude that CTD induces cytotoxicity by targeting Cdc1 activity in GPI-anchor remodeling in the ER. Glycosylphosphatidylinositol (GPI) 3 anchor biosynthesis is an essential and conserved pathway in eukaryotes. GPI-anchor

Cantharidin downregulates PSD1 expression and inhibits autophagic flux in yeast cells

“…Psd1p of mitochondria contributes majorly to the cellular PE pool [51,52]. In line with these observations and previous finding which shows that PSD1 shows synthetic lethality with CRG1 and increased sensitivity towards CAN [9] , we reasoned that CAN might be targeting PSD1 for exhibiting its toxicity. In this regard, we allowed the wildtype yeast cells to grow in the presence or absence of increasing doses of CAN (50,100,150 and 200 µM) for 3 hours.…”

Targeted Lipidomics Reveal the Effect of Perchlorate on Lipid Profiles in Liver of High-Fat Diet Mice

“…PE is synthesized in vivo by methylation to 1-methylphosphatidylethanolamine (PMME), which is then methylated to produce dimethyl phosphatidylethanolamine (PDME), and PDME is synthesized under the action of enzymes to PC ( 28 ). The phospholipase PLA2 hydrolyzes PC to LPC, and LPC and PC can be interconverted ( 29 ). It has been demonstrated that PC mediates the promotion of cell proliferation, growth and programmed cell death ( 30 ).…”

Sodium cantharidate targets STAT3 and abrogates EGFR inhibitor resistance in osteosarcoma

“…Research over the last two decades showed that cantharidin and its derivatives can promote tumor regression in multiple cancers via different mechanisms, and numerous analogues were designed to improve efficacy and safety in anti-cancer regimens [12,40]. Targets of cantharidin include protein phosphatases [41][42][43], glutathione S-transferases [44], STAT3 [16,45], Akt [46], and cell division control protein 1 (CDC1) [47]. With focus on the concomitant activation of EGFR and STAT3 as determinants of osteosarcoma progression, we investigated the mechanisms underlying the anticancer effects of SC, a cantharidin analogue, alone and in combination with the EGFR inhibitor erlotinib.…”