Desmethylclomipramine triggers mitochondrial damage and death in TGF-β-induced mesenchymal type of A549 cells

Fu Chia Shih, Chiou Feng Lin, Yu Chih Wu, Chun Chun Hsu, Bing Chang Chen, Yu Chen Chang, Yu Syuan Lin, Rahmat Dani Satria, Pei Yun Lin, Chia Ling Chen

研究成果: 雜誌貢獻文章同行評審

1 引文 斯高帕斯(Scopus)

摘要

Lung cancer is the leading cause of cancer deaths, where the metastasis often causes chemodrug resistance and leads to recurrence after treatment. Desmethylclomipramine (DCMI), a bioactive metabolite of clomipramine, shows the therapeutic efficacy with antidepressive agency as well as potential cytostatic effects on lung cancer cells. Here, we demonstrated that DCMI effectively caused transforming growth factor (TGF)-β1-mediated mesenchymal type of A549 cells to undergo mitochondrial death via myeloid cell leukemia-1 (Mcl-1) suppression and activation of truncated Bid (tBid). TGF-β1 induced epithelial mesenchymal transition in A549 cells with the increase of fibronectin and decrease of E-cadherin, the activation of Akt/glycogen synthase kinase-3β (GSK-β)/Mcl-1 axis, and the hypo-responsiveness to cisplatin. DCMI initiated a dose-dependent cytotoxicity on TGF-β1-mediated mesenchymal type of A549 cells through inactivating Akt/GSK-β/Mcl-1 axis, in which mitochondria instability and caspase-9/3 activation also occurred concurrently. Pharmacological inhibition of caspase-8 and cathepsin B partly reversed tBid expression and mitochondrial damage to further attenuate DCMI-mediated cytotoxicity. Additionally, DCMI presented partial therapeutic effects in treating mesenchymal type of A549 tumor bearing nude mice through an acceleration of cancer cell death. Taken together, DCMI exerts antitumor effects via initiating the mechanisms of Akt/GSK-β/Mcl-1 inactivation and cathepsin B/caspase-8-regulated mitochondrial death, which suggests its potential role in mesenchymal type of cancer cell therapy.
原文英語
文章編號122817
期刊Life Sciences
351
DOIs
出版狀態已發佈 - 8月 15 2024

ASJC Scopus subject areas

  • 一般生物化學,遺傳學和分子生物學
  • 一般藥理學、毒理學和製藥學

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