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KMID : 0043320190420100890
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Archives of Pharmacal Research
2019 Volume.42 No. 10 p.890 ~ p.901
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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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Lee Yoon-Jin
Park Kwan-Sik
Heo Su-Hak
Nam Hae-Seon
Cho Moon-Kyun
Lee Sang-Han
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Abstract
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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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KEYWORD
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Pifithrin-μ, Heat shock protein 70, Necroptosis, Epithelial?mesenchymal transition, p53, Malignant mesothelioma
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