T-2 Toxin Exposure Induces Apoptosis in TM3 Cells by Inhibiting Mammalian Target of Rapamycin/Serine/Threonine Protein Kinase(mTORC2/AKT) to Promote Ca2+Production.

Ji Wang,Jine Yi,Chenglin Yang,Zhihang Yuan,Jing Wu

doi:10.3390/ijms19113360

Ji Wang, Jine Yi + Show 3 more

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https://doi.org/10.3390/ijms19113360

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Abstract

Although mTOR (the mammalian target of rapamycin) can regulate intracellular free Ca2+concentration in normal cultured podocytes, it remains elusive as to how mTORC2/AKT-mediated Ca2+participates in the process of T-2 toxin-induced apoptosis. The potential signaling responsible for intracellular Ca2+ concentration changes was investigated using immunoblot assays in an in vitro model of TM3 cell injury induced by T-2 toxin. Changes in Ca2+ were assessed using the Ca2+-sensitive fluorescent indictor dye Fura 2-AM. The cytotoxicity of TM3 cells was assessed with an MTT bioassay, and apoptosis was measured using Annexin V-FITC staining. Following T-2 toxin treatment, the growth of cells, phospho-mTORSer2481, phospho-mTORSer2448, and phospho-AktSer473 were significantly decreased in a time-dependent manner, whereas Ca2+ and apoptosis were increased. T-2 toxin-induced apoptosis was prevented by BAPTA-AM (a Ca2+chelator) and MHY1485 (an mTOR activator), and the application of mTOR activator MHY1485 also prevented the increase of intracellular free Ca2+concentration in TM3 cells. Our results strongly suggest that T-2 toxin exposure induces apoptosis in TM3 cells by inhibiting mTORC2/AKT to promote Ca2+ production.

Highlights

Mycotoxins are a very numerous and diverse group of secondary metabolites of molds that cause toxicological effects in mammals [1]
Our previous studies found that T-2 toxin decreased antioxidant scavenging enzymes, increased lipid peroxidation and ROS production, and contributed to TM3 cells apoptosis
Activating the ROS-mediated mitochondrial pathway is the mechanism of T-2 toxin-induce apoptosis [29]

Summary

Introduction

Mycotoxins are a very numerous and diverse group of secondary metabolites of molds that cause toxicological effects in mammals [1]. It is estimated that before or after harvest, approximately 25% of the world’s agricultural commodities are contaminated to some extent with mycotoxins [2]. One of the most notorious mycotoxins that present a potential hazard to human and animal health is T-2 toxin. This toxin is a structural derivative of the trichothecene ring system; trichothecenes are synthetized by several Fusarium species, such as F. sporotrichioides, F. langsethiae, F. acuminatum, and F. poae [3]. Parenteral, and cutaneous exposure to T-2 toxin manifests deleterious effects in some experimental animal modes, which exhibit apoptosis in various tissues and organs, including

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