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Pifithrin-μ induces necroptosis through oxidative mitochondrial damage but accompanies epithelial–mesenchymal transition-like phenomenon in malignant mesothelioma cells under lactic acidosis

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Abstract

Heat shock protein 70 (HSP70), a chaperone protein associated with tumorigenesis and chemoresistance, has attracted significant attention as a potential therapeutic target for the development of anticancer drugs. Here, the effects of pifithrin-μ, an effective dual inhibitor of HSP70 and p53, on anticancer activities and epithelial–mesenchymal transition (EMT) were investigated in malignant mesothelioma (MM) cells. MSTO-211HAcT cells, pre-incubated in a medium containing lactic acid, showed more potent resistance to cisplatin and gemcitabine, compared with their acid-sensitive parental MSTO-211H cells. Pifithrin-μ treatment induced both apoptosis and necroptosis, which were accompanied by an EMT-like phenomenon, as evidenced by an elongated cell morphology, decreased levels of epithelial cell markers including E-cadherin, claudin-1, and β-catenin, increased levels of mesenchymal markers including Snail, Slug, and vimentin, and increased cell migratory property. Moreover, pifithrin-μ increased intracellular ROS levels, which is associated with mitochondrial dysfunction and decreased cellular ATP content. A series of changes caused by pifithrin-μ treatment were effectively restored by lowering the ROS level through pretreatment with N-acetylcysteine. Collectively, our results suggest that pifithrin-μ may promote the metastatic behavior of surviving cells by triggering the EMT, despite its effective cell-killing action against MM cells, possibly linked to oxidative mitochondrial dysfunction and ATP depletion.

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Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea, funded by the Ministry of Education (No. NRF-2018R1D1A1B07046129).

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Correspondence to Sang-Han Lee.

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Dr. Heo attends CnK Pharma but declares that no support, financial or otherwise, has been received from CnK pharma for this research. Other authors state that they have no conflicts of interest.

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Lee, YJ., Park, KS., Heo, SH. et al. Pifithrin-μ induces necroptosis through oxidative mitochondrial damage but accompanies epithelial–mesenchymal transition-like phenomenon in malignant mesothelioma cells under lactic acidosis. Arch. Pharm. Res. 42, 890–901 (2019). https://doi.org/10.1007/s12272-019-01181-6

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