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Triclosan induces ROS-dependent cell death and autophagy in A375 melanoma cells.

ABSTRACT: Melanoma is a common type of cutaneous tumor, but current drug treatments do not satisfy clinical practice requirements. At present, mitochondrial uncoupling is an effective antitumor treatment. Triclosan, a common antimicrobial, also acts as a mitochondrial uncoupler. The aims of the present study were to investigate the effects of triclosan on melanoma cells and the underlying mechanisms. Mitochondrial membrane potential (MMP), mitochondrial morphology, mitochondrial reactive oxygen species (mito-ROS), intracellular superoxide anion and [Ca2+]i were measured using confocal microscopy. It was found that triclosan application was associated with decreased A375 cell viability in a dose- and time-dependent manner and these effects may have cell specificity. Furthermore, triclosan induced MMP depolarization, ATP content decrease, mito-ROS and [Ca2+]i level increases, excessive mitochondrial fission, AMP-activated protein kinase (AMPK) activation and STAT3 inhibition. Moreover, these aforementioned effects were reversed by acetylcysteine treatment. Triclosan acute treatment also induced mitochondrial swelling, which was reversed after AMPK-knockdown associated with [Ca2+]i overload. Cell death was caused by STAT3 inhibition but not AMPK activation. Moreover, triclosan induced autophagy via the ROS/AMPK/p62/microtubule-associated protein 1A/1B-light chain 3 (LC3) signaling pathway, which may serve a role in feedback protection. Collectively, the present results suggested that triclosan increased mito-ROS production in melanoma cells, following induced cell death via the STAT3/Bcl-2 pathway and autophagy via the AMPK/p62/LC3 pathway.

SUBMITTER: Jin J

PROVIDER: S-EPMC7436935 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Triclosan induces ROS-dependent cell death and autophagy in A375 melanoma cells.

Jin Jing J Chen Naiwen N Pan Huan H Xie Wenhua W Xu Hong H Lei Siyu S Guo Zhiqin Z Ding Renye R He Yi Y Gao Jinlai J

Oncology letters 20200730 4

Melanoma is a common type of cutaneous tumor, but current drug treatments do not satisfy clinical practice requirements. At present, mitochondrial uncoupling is an effective antitumor treatment. Triclosan, a common antimicrobial, also acts as a mitochondrial uncoupler. The aims of the present study were to investigate the effects of triclosan on melanoma cells and the underlying mechanisms. Mitochondrial membrane potential (MMP), mitochondrial morphology, mitochondrial reactive oxygen species (m ...[more]

PMID: 32863906

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Project description:The innate response of melanocytes to exogenous or endogenous stress stimuli like extreme pH and temperature, metabolite and oxygen deficiency or a high UV dose initiates a cellular stress response. This process activates adaptive processes to minimize the negative impact of the stressor on the pigment cell. Under physiological conditions, a non-cancer cell is directed to apoptosis if the stressor persists. However, malignant melanoma cells will survive persistent stress thanks to distinct "cancerous" signaling pathways (e.g. MEK) and transcription factors that regulate the expression of so-called "survival genes" (e.g. HIF, MITF). In this survival response of cancer cells, MEK pathway directs melanoma cells to deregulate mitochondrial metabolism, to accumulate reduced species (NADH), and to centralize metabolism in the cytosol. The aim of this work was to study the effect of gene silencing in malignant melanoma A375 cells on metabolic processes in cytosol and mitochondria. Gene silencing of HIF-1α, and miR-210 in normoxia and pseudohypoxia, and analysis of its effect on MITF-M, and PDHA1 expression. Detection of cytosolic NADH by Peredox-mCherry Assay. Detection of OCR, and ECAR using Seahorse XF96. Measurement of produced O2•- with MitoTracker Red CMXRos. 1H NMR analysis of metabolites present in cell suspension, and medium. By gene silencing of HIF-1α and miR-210 the expression of PDHA1 was upregulated while that of MITF-M was downregulated, yielding acceleration of mitochondrial respiratory activity and thus elimination of ROS. Hence, we detected a significantly reduced A375 cell viability, an increase in alanine, inositol, nucleotides, and other metabolites that together define apoptosis. Based on the results of measurements of mitochondrial resipiratory activity, ROS production, and changes in the metabolites obtained in cells under the observed conditions, we concluded that silencing of HIF-1α and miR-210 yields apoptosis and, ultimately, apoptotic cell death in A375 melanoma cells.

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Triclosan induces ROS-dependent cell death and autophagy in A375 melanoma cells.

Publications

Triclosan induces ROS-dependent cell death and autophagy in A375 melanoma cells.

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