Promotion of Melanoma Cell Invasion and Tumor Metastasis by Microcystin-LR via Phosphatidylinositol 3-Kinase/AKT Pathway

Xu, Pengfei; Zhang, Xuxiang; Miao, Chen; Fu, Ziyi; Li, Zhengrong; Zhang, Gen; Zheng, Maqing; Liu, Yuefang; Yang, Liuyan; Wang, Ting

doi:10.1021/es4007228

Cited by 19 publications

(27 citation statements)

References 39 publications

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“…PP2A is an important enzyme which dephosphorylates Akt at these residues . The activation of Akt induced by MC‐LR owing to inhibition of PP2A has been reported by many groups, including in our previous work . In the current study, Akt activation was observed in HL7702 cells and in MC‐LR‐treated mice' livers owing to the finding that the phosphorylation level of Akt at Thr 308 and Ser 473 was significantly increased.…”

Section: Discussionsupporting

confidence: 66%

The effects of short‐term treatment of microcystin‐LR on the insulin pathway in both the HL7702 cell line and livers of mice

Huang

Chen

et al. 2020

Environmental Toxicology

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Our previous work indicated exposure of Human liver cell 7702 (HL7702) cells to Microcystin-leucine-arginine (MC-LR) for 24 hours can disrupt insulin (INS) signaling by the hyperphosphorylation of specific proteins. For further exploring the timedependent effect posed by MC-LR on this pathway, in the current study, HL7702 cells together with mice were exposed to the MC-LR with different concentrations under short-term treatment, and then, protein phosphatase 2A (PP2A) activity and expression of proteins related to INS signaling, as well as the characteristics of their action in the liver, were investigated. The results indicated, in HL7702 cells with 0.5, 1, and 6 hours of treatment by MC-LR, PP2A activity showed an obvious decrease in a time and concentration-dependent manner. While the total protein level of Akt, glycogen synthase kinase 3 (GSK-3), and glycogen synthase remained unchanged, GSK-3 and Akt phosphorylation increased significantly. In livers of mice with 1 hour of intraperitoneal injection with MC-LR, a similar change in these proteins was observed. In addition, the levels of total IRS1 and p-IRS1 at serine sites showed decreasing and increasing trends,respectively, and the hematoxylin and eosin staining showed that liver tissues of mice in the maximum-dose group exhibited obvious hepatocyte degeneration and hemorrhage. Our results further proved that short-term treatment with MC-LR can inhibit PP2A activity and disrupt INS signaling proteins' phosphorylation level, thereby interfering with the INS pathway. Our findings provide a helpful understanding of the toxic effects posed by MC-LR on the glucose metabolism of liver via interference with the INS signaling pathway. K E Y W O R D S INS signaling proteins, microcystin-LR, PP2A, short-term treatment 1 | INTRODUCTION Microcystin (MC) refers to a group of monocyclic heptapeptides toxins generated via cyanobacteria and are largely released in waterbodies where cyanobacteria bloom occurs. The increased occurrence of cyanobacteria bloom due to eutrophication emphasizes the need for studying the toxic effects posed by MCs on humans and animals. To date, over 90 various structural analogues of the MC have been documented, there into, Microcystin-leucine-arginine (MC-LR) exhibits a wide distribution and strong toxicity in the MC family. 1 MC-LR is a highly liverspecific toxin and can induce generalized hepatocyte degeneration in case of chronic poisoning, leading to progressive fibrosis, necrosis, as well as infiltration of mononuclear leukocyte, 2 while as to its acute poisoning, MC-LR can disorganize the hepatic architecture rapidly, break Pu Huang and Kele Chen are the co-first authors.

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Section: Discussionsupporting

confidence: 66%

The effects of short‐term treatment of microcystin‐LR on the insulin pathway in both the HL7702 cell line and livers of mice

Huang

Chen

et al. 2020

Environmental Toxicology

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“…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, ). Recent studies have demonstrated that MCLR can promote cell invasion and tumor metastasis (Zhang et al, ; Xu et al, ). Xu et al reported that MCLR can promote MDA‐MB‐435 cell invasion and metastasis via the PI3‐K/AKT pathway.…”

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

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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.

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“…Epidemiological studies have demonstrated that MCs may contribute to a higher incidence of primary human carcinomas (Zhou et al, 2002). Experimental evidence also supports that MC-LR may not only act as a tumor initiator, but also stimulate the invasion and migration of cancer cells (Xu et al, 2013; Zhang et al, 2012). It is also documented that MC-LR can promote fibrosis (Milutinovic et al, 2006).…”

Section: Discussionmentioning

confidence: 73%

“…The activation of the PI3K/Akt and MEK/ERK signaling pathways have been suggested to be involved in the apoptosis induced by MC-LR (Wang et al, 2012). Moreover, MC-LR exposure could increase melanoma cell invasion and tumor metastasis as well as EMTbyactivating PI3K/AKT (Tsukamoto et al, 2013; Xu et al, 2013). In addition, it is possible that the activated MAPK signaling pathways play important roles in modulating MC-LR-induced cellular stress responses (Carreras and Poderoso, 2007).…”

Section: Discussionmentioning

confidence: 99%

The toxic effects of microcystin-LR on mouse lungs and alveolar type II epithelial cells

Wang

Yin

et al. 2016

Toxicon

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Objectives Microcystin-leucine arginine (MC-LR) is produced by cyanobacteria and can accumulate in lungs through blood circulation. However, the effect of MC-LR on lung remains unclear. In this study, we investigated the chronic, low-dose effect of MC-LR on mouse lung tissues and the influence of MC-LR on mouse alveolar type II epithelial cells (ATII cells). Methods MC-LR was orally administered to mice at 0, 1, 10, and 40 μg/L for 6 consecutive months and mouse lungs were obtained for histopathological and immunoblot analysis. ATII cells were cultured in various concentrations of MC-LR (0, 0.5, 5, 50, 500 nmol/L) for indicated time and the cell viability and proteins change were tested. Results Our study revealed that the chronic, low-dose MC-LR exposure induced alveolar collapse and lung cell apoptosis as well as the breach of cell junction integrity. Furthermore, following treatment with MC-LR, ATII cells could uptake MC-LR, resulting in apoptosis and disruption of cell junction integrity. Conclusions These data support the toxic potential of low-dose MC-LR in rendering chronic injury to lung tissues.

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Promotion of Melanoma Cell Invasion and Tumor Metastasis by Microcystin-LR via Phosphatidylinositol 3-Kinase/AKT Pathway

Cited by 19 publications

References 39 publications

The effects of short‐term treatment of microcystin‐LR on the insulin pathway in both the HL7702 cell line and livers of mice

The effects of short‐term treatment of microcystin‐LR on the insulin pathway in both the HL7702 cell line and livers of mice

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

The toxic effects of microcystin-LR on mouse lungs and alveolar type II epithelial cells

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