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

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

J Biol Chem. 2019 Jan 18;:

Authors: Sahu PK, Tomar RS

Abstract
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, cellwall 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 glycophosphatidylinositol (GPI)-anchored proteins. A CTD-dependent genetic interaction profile of CRG1 revealed that 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. Furthermore, 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 Cdc1activity in GPI-anchor remodeling in the ER.

PMID: 30659098 [PubMed - as supplied by publisher]

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