Microcystin-LR Induces Apoptosis via NF-κB /iNOS Pathway in INS-1 Cells

Abstract

Cyanobacterial toxins, especially the microcystins, are found in eutrophied waters throughout the world, and their potential to impact on human and animal health is a cause for concern. Microcystin-LR (MC-LR) is one of the common toxic microcystin congeners and occurs frequently in diverse water systems. Recent work suggested that apoptosis plays a major role in the toxic effects induced by MC-LR in hepatocytes. However, the roles of MC-LR in pancreatic beta cells have not been fully established. The aim of the present study was to assess possible in vitro effects of MC-LR on cell apoptosis in the rat insulinoma cell line, INS-1. Our results demonstrated that MC-LR promoted selectively activation of NF-κB (increasing nuclear p50/p65 translocation) and increased the mRNA and protein levels of induced nitric oxide synthase (iNOS). The chronic treatment with MC-LR stimulated nitric oxide (NO) production derived from iNOS and induced apoptosis in a dose dependent manner in INS-1 cells. Meanwhile, this effect was inhibited by the NF-κB inhibitor PDTC, which reversed the apoptosis induced by MC-LR. Our observations indicate that MC-LR induced cell apoptosis via an iNOS-dependent pathway. A well-known nuclear transcription factor, NF-κB, is activated and mediates intracellular nitric oxide synthesis. We suggest that the apoptosis induced by chronic MC-LR in vivo presents a possible cause of β-cell dysfunction, as a key environmental factor in the development of diabetes mellitus.

New Insights on the Mode of Action of Microcystins in Animal Cells - A Review

“…Feng et al [61] showed that MC-LR induced Fas receptor (Fas) and Fas ligand (FasL) expression, at both mRNA and protein levels system, are mediated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B), a known protein complex that functions as a transcription factor and plays a fundamental role in the immune response to infection and is involved in the response to several other cellular stimuli [62], thus leading to cellular apoptosis in HepG2 cells. In agreement with this the severe stress effects and apoptosis in the rat insulinoma cell line INS-1 upon chronic exposure to MC were shown to be correlated with the selective activation of NF-κB [63].…”

Astaxanthin Attenuates the Apoptosis of Retinal Ganglion Cells in db/db Mice by Inhibition of Oxidative Stress

“…Dysfunction induced by the decreased population of cells is regarded as an important factor in the pathogenesis of various metabolic diseases [18,19]. To determine the effects of astaxanthin on RGCs, the apoptosis was determined using tunel assays.…”

The role of GSH in microcystin‐induced apoptosis in rat liver: Involvement of oxidative stress and NF‐κB

“…Transcription factor nuclear factor‐kappa B (NF‐κB), which is sensitive to ROS production and oxidative stress, is thought to play a key role in the development of several liver diseases including hepatitis, liver fibrosis and cirrhosis, and hepatocellular carcinoma (Sun and Karin, ; Morgan and Liu, ). Recent studies have reported that MC‐LR induced activation of NF‐κB in HepG2 cells (Feng et al, ), rat insulinoma cells (INS‐1) (Ji et al, ), melanoma cells (MDA‐MB‐435) (Zhang et al, ), human hepatoma cells (Huh7) (Christen et al, ), mice hepatocytes (Zhang et al, ), and HeLa cells (Chen et al, ). MC‐LR promoted nuclear translocation and activation of p65 subunit of NF‐κB, resulting in cellular apoptosis.…”

“…MC‐LR promoted nuclear translocation and activation of p65 subunit of NF‐κB, resulting in cellular apoptosis. Meanwhile, this effect was inhibited by transfection of siRNA against p65 in HepG2 cells (Feng et al, ) and pretreatment with ammonium pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF‐κB activation, in INS‐1 cells (Ji et al, ). Christen et al () demonstrated that MC‐LR activates NF‐κB, induces IFN‐α and TNF‐α expression, and may contribute to tumor promotion and induction of apoptosis in Huh7 cells.…”