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• W3201161569 abstract "The highly cytotoxic marine natural product callyspongiolide holds great promise as a warhead of antibody-drug conjugate in cancer therapeutics; however, the mechanism underlying its cytotoxicity remains unclear. To elucidate how callyspongiolide kills cells, we employed label-free target identification with thermal stability-shift-based fluorescence difference in two-dimensional (2-D) gel electrophoresis (TS-FITGE), which allowed observation of a unique phenomenon of protein-spot separation on 2-D gels upon treatment with callyspongiolide at increasing temperatures. During our exploration of what proteins were associated with this phenomenon as well as why it happens, we found that callyspongiolide induces mitochondrial/lysosomal dysfunction and autophagy inhibition. Moreover, molecular biology studies revealed that callyspongiolide causes lysosomal dysfunction, which induces cellular iron depletion and leads to mitochondrial dysfunction and subsequent cytotoxicity. Notably, these effects were rescued through iron supplementation. Although our approach was unable to reveal the direct protein targets of callyspongiolide, unique phenomena observed only by TS-FITGE provided critical insight into the mechanism of action of callyspongiolide and specifically its cytotoxic activity via induction of mitochondrial dysfunction through cellular iron depletion caused by lysosomal deacidification, which occurred independent of known programmed cell death pathways." @default.
• W3201161569 created "2021-09-27" @default.
• W3201161569 creator A5044752551 @default.
• W3201161569 creator A5091055050 @default.
• W3201161569 date "2021-09-23" @default.
• W3201161569 modified "2023-10-17" @default.
• W3201161569 title "Callyspongiolide kills cells by inducing mitochondrial dysfunction via cellular iron depletion" @default.
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• W3201161569 doi "https://doi.org/10.1038/s42003-021-02643-8" @default.
• W3201161569 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8460830" @default.
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• W3201161569 hasPublicationYear "2021" @default.
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