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Development of a Retinal-Based Probe for the Profiling of Retinaldehyde Dehydrogenases in Cancer Cells

2019; American Chemical Society; Volume: 5; Issue: 12 Linguagem: Inglês

10.1021/acscentsci.9b01022

2374-7951

Sebastiaan T. A. Koenders, Lukas S. Wijaya, Martje N. Erkelens, Alexander T. Bakker, Vera E. van der Noord, Eva J. van Rooden, Lindsey Burggraaff, Pasquale C. Putter, Else Botter, Kim Wals, Hans van den Elst, Hans den Dulk, Bogdan I. Florea, Bob van de Water, Gerard J. P. van Westen, Reina E. Mebius, Herman S. Overkleeft, Sylvia E. Le Dévédec, Mario van der Stelt,

Receptor Mechanisms and Signaling

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.