Development of a Retinal-Based Probe for the Profiling of Retinaldehyde Dehydrogenases in Cancer Cells
| Autor: | Hans den Dulk, Reina E Mebius, Eva J. van Rooden, Hans van den Elst, Pasquale C Putter, Bob van de Water, Else Botter, Gerard J. P. van Westen, Alexander T Bakker, Vera E. van der Noord, Bogdan I. Florea, Mario van der Stelt, Kim Wals, Sylvia E. Le Dévédec, Sebastiaan T A Koenders, Herman S. Overkleeft, Lukas S Wijaya, Martje N. Erkelens, Lindsey Burggraaff |
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| Přispěvatelé: | Molecular cell biology and Immunology, AII - Cancer immunology, CCA - Cancer biology and immunology, AGEM - Digestive immunity |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
biology
010405 organic chemistry Drug discovery General Chemical Engineering Cellular differentiation Retinoic acid Aldehyde dehydrogenase Retinal General Chemistry 010402 general chemistry Proteomics 01 natural sciences 0104 chemical sciences ALDH1A1 chemistry.chemical_compound Chemistry chemistry Biochemistry Cancer cell biology.protein QD1-999 Research Article |
| Zdroj: | ACS Central Science, Vol 5, Iss 12, Pp 1965-1974 (2019) ACS Central Science, 5(12), 1965-1974 ACS Central Science, 5(12), 1965-1974. American Chemical Society ACS Central Science Koenders, S T A, Wijaya, L S, Erkelens, M N, Bakker, A T, van der Noord, V E, van Rooden, E J, Burggraaff, L, Putter, P C, Botter, E, Wals, K, van den Elst, H, den Dulk, H, Florea, B I, van de Water, B, van Westen, G J P, Mebius, R E, Overkleeft, H S, Le Dévédec, S E & van der Stelt, M 2019, ' Development of a Retinal-Based Probe for the Profiling of Retinaldehyde Dehydrogenases in Cancer Cells ', ACS Central Science, vol. 5, no. 12, pp. 1965-1974 . https://doi.org/10.1021/acscentsci.9b01022 |
| ISSN: | 2374-7951 2374-7943 |
| Popis: | Retinaldehyde dehydrogenases belong to a superfamily of enzymes that regulate cell differentiation and are responsible for detoxification of anticancer drugs. Chemical tools and methods are of great utility to visualize and quantify aldehyde dehydrogenase (ALDH) activity in health and disease. Here, we present the discovery of a first-in-class chemical probe based on retinal, the endogenous substrate of retinal ALDHs. We unveil the utility of this probe in quantitating ALDH isozyme activity in a panel of cancer cells via both fluorescence and chemical proteomic approaches. We demonstrate that our probe is superior to the widely used ALDEFLUOR assay to explain the ability of breast cancer (stem) cells to produce all-trans retinoic acid. Furthermore, our probe revealed the cellular selectivity profile of an advanced ALDH1A1 inhibitor, thereby prompting us to investigate the nature of its cytotoxicity. Our results showcase the application of substrate-based probes in interrogating pathologically relevant enzyme activities. They also highlight the general power of chemical proteomics in driving the discovery of new biological insights and its utility to guide drug discovery efforts. LEI-945 is a first-in-class retinal-based probe that enables profiling aldehyde dehydrogenase activity in living cancer cells and maps the selectivity profile of ALDH inhibitors. |
| Databáze: | OpenAIRE |
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