Effects of microcystin-LR on Saccharomyces cerevisiae growth, oxidative stress and apoptosis

Valério, Elisabete; Vilares, Arminda; Campos, Alexandre; Pereira, Paulo; Vasconcelos, Vı́tor

doi:10.1016/j.toxicon.2014.08.059

Cited by 17 publications

(20 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many studies suggest that MCLR affects cell apoptosis, oxidative stress, cell growth, and cell invasion (Fu and Xu, ; Zhang et al, ; Valerio et al, ). We found that stimulation with MCLR induced apoptosis in HEK293, possibly through anoikis (Grossmann, ; Wazir et al, ), and that MCLR can promote proliferation through the activation of the Akt/S6K1 pathway in HL7702 (Liu et al, ).…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 2A inhibition and subsequent cytoskeleton reorganization contributes to cell migration caused by microcystin-LR in human laryngeal epithelial cells (Hep-2)

et al. 2016

View full text Add to dashboard Cite

The major toxic mechanism of Microcystin-LR is inhibition of the activity of protein phosphatase 2A (PP2A), resulting in a series of cytotoxic effects. Our previous studies have demonstrated that microcystin-LR (MCLR) induced very different molecular effects in normal cells and the tumor cell line SMMC7721. To further explore the MCLR toxicity mechanism in tumor cells, human laryngeal epithelial cells (Hep-2) was examined in this study. Western blot, immunofluorescence, immunoprecipitation, and transwell migration assay were used to detect the effects of MCLR on PP2A activity, PP2A substrates, cytoskeleton, and cell migration. The results showed that the protein level of PP2A subunits and the posttranslational modification of the catalytic subunit were altered and that the binding of the AC core enzyme as well as the binding of PP2A/C and α4, was also affected. As PP2A substrates, the phosphorylation of MAPK pathway members, p38, ERK1/2, and the cytoskeleton-associated proteins, Hsp27, VASP, Tau, and Ezrin were increased. Furthermore, MCLR induced reorganization of the cytoskeleton and promoted cell migration. Taken together, direct covalent binding to PP2A/C, alteration of the protein levels and posttranslational modification, as well as the binding of subunits, are the main pattern for the effects of MCLR on PP2A in Hep-2. A dose-dependent change in p-Tau and p-Ezrin due to PP2A inhibition may contribute to the changes in the cytoskeleton and be related to the cell migration in Hep-2. Our data provide a comprehensive exposition of the MCLR mechanism on tumor cells. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 890-903, 2017.

show abstract

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 2A inhibition and subsequent cytoskeleton reorganization contributes to cell migration caused by microcystin-LR in human laryngeal epithelial cells (Hep-2)

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The main mode of action of MCs has been attributed to the highly specific inhibition of serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A), which in turn causes an excessive phosphorylation of proteins (MacKintosh et al, 1990;Tencalla and Dietrich, 1997). Recent evidences also suggested that excessive production of reactive oxygen species (ROS) and oxidative stress played a significant role in MCs toxicity in yeast (Valério et al, 2014), rat (Moreno et al, 2005;Chen et al, 2015), mice (Jayaraj et al, 2006), and fish (Jiang et al, 2011(Jiang et al, , 2013Pavagadhi et al, 2012). It has been suggested that either of the above mechanisms could induce cytoskeletal damage (Milutinović et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Involvement of oxidative stress and cytoskeletal disruption in microcystin-induced apoptosis in CIK cells

et al. 2015

View full text Add to dashboard Cite

“…The repression of this protein has been related with increased sensitivity of cells to DNA-damaging agents [ 32 ]. Previously, we detected the increase of the intracellular ROS levels when S. cerevisiae was exposed, in similar conditions, to MC-LR [ 15 ]. Increase of ROS was verified even for the lowest MC-LR concentration (1 nM) [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we detected the increase of the intracellular ROS levels when S. cerevisiae was exposed, in similar conditions, to MC-LR [ 15 ]. Increase of ROS was verified even for the lowest MC-LR concentration (1 nM) [ 15 ]. Our previous results thus support our current hypothesis that MC-LR caused an increase in intracellular ROS.…”

Section: Discussionmentioning

confidence: 99%

“…These studies showed, for instance, that MC-LR induced an increase of H 2 O 2 in S. cerevisiae as the main ROS [ 15 ]. Moreover, signs of apoptosis and some cell death by necrosis were also detected after exposing the yeast cells to MC-LR [ 15 ], consistent with the responses observed in mammal cells exposed to MC-LR [ 16 ]. Furthermore, a set of 14 proteins affected by MC-LR were revealed by proteomics.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

New Insights in Saccharomyces cerevisiae Response to the Cyanotoxin Microcystin-LR, Revealed by Proteomics and Gene Expression

Valério

Barreiros

Rodrigues

et al. 2020

Toxins

Self Cite

View full text Add to dashboard Cite

Microcystins (MCs) are hepatotoxins produced by some cyanobacteria. They are cyclic peptides that inhibit the serine/threonine protein phosphatases (PPs) PP1 and PP2A, especially PP2A. The inhibition of PP2A triggers a series of molecular events, which are responsible for most MC cytotoxic and genotoxic effects on animal cells. It is also known that MCs induce oxidative stress in cells due to the production of reactive oxygen species (ROS). However, a complete characterization of the toxic effects of MCs is still not accomplished. This study aimed to clarify additional molecular mechanisms involved in MC-LR toxicity, using Saccharomyces cerevisiae as eukaryotic model organism. First, a shotgun proteomic analysis of S. cerevisiae VL3 cells response to 1 nM, 10 nM, 100 nM, and 1 µM MC-LR was undertaken and compared to the control (cells not exposed to MC-LR). This analysis revealed a high number of proteins differentially expressed related with gene translation and DNA replication stress; oxidative stress; cell cycle regulation and carbohydrate metabolism. Inference of genotoxic effects of S. cerevisiae VL3 cells exposed to different concentrations of MC-LR were evaluated by analyzing the expression of genes Apn1, Apn2, Rad27, Ntg1, and Ntg2 (from the Base Excision Repair (BER) DNA repair system) using the Real-Time RT-qPCR technique. These genes displayed alterations after exposure to MC-LR, particularly the Apn1/Apn2/Rad27, pointing out effects of MC-LR in the Base Excision Repair system (BER). Overall, this study supports the role of oxidative stress and DNA replication stress as important molecular mechanisms of MC-LR toxicity. Moreover, this study showed that even at low-concentration, MC-LR can induce significant changes in the yeast proteome and in gene expression.

show abstract

Effects of microcystin-LR on Saccharomyces cerevisiae growth, oxidative stress and apoptosis

Cited by 17 publications

References 38 publications

Protein phosphatase 2A inhibition and subsequent cytoskeleton reorganization contributes to cell migration caused by microcystin-LR in human laryngeal epithelial cells (Hep-2)

Protein phosphatase 2A inhibition and subsequent cytoskeleton reorganization contributes to cell migration caused by microcystin-LR in human laryngeal epithelial cells (Hep-2)

Involvement of oxidative stress and cytoskeletal disruption in microcystin-induced apoptosis in CIK cells

New Insights in Saccharomyces cerevisiae Response to the Cyanotoxin Microcystin-LR, Revealed by Proteomics and Gene Expression

Contact Info

Product

Resources

About