Papalazarou, V. et al. (2023) Phenotypic profiling of solute carriers characterizes serine transport in cancer. Nature Metabolism, 5(12), pp. 2148-2168. (doi: 10.1038/s42255-023-00936-2) (PMID:38066114) (PMCID:PMC10730406)
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Abstract
Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.
| Item Type: | Articles |
|---|---|
| Additional Information: | The authors thank Biological Services facility staff at the Cancer Research UK (CRUK) Beatson Institute, funded by CRUK (A18076, A17196 and A31287). We also thank the following: P. A. Gammage for advice regarding mitochondrial fractionation for protein analysis; D. A. Tennant for sharing his protocol of cellular compartmentalization and GC–MS analysis; J. Macrae and the Metabolomics STP of the Francis Crick Institute; M. Howell and the High-Throughput Screening STP of the Francis Crick Institute and the Advanced Light Microscopy STP of the Francis Crick Institute. V.P., A.H.U., A.C.N., T.Z. and O.D.K.M. were funded by a CRUK Career Development Fellowship awarded to O.D.K.M. (C53309/A19702). M.F. was funded by an EMBO Long-Term Fellowship (EMBO ALTF 276-2019). K.B. and D.A. were core funded by CRUK (A17196, A29799 and A31287). L.M. and E.S. were core funded by CRUK (A17196). K.H.V. is supported by the Francis Crick Institute, which receives its core funding from CRUK (CC2073), the UK Medical Research Council (CC2073) and the Wellcome Trust (CC2073). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Zhang, Mr Tong and Newman, Dr Alice and McGarry, Ms Lynn and Blyth, Professor Karen and Athineos, Mr Dimitris and Vousden, Karen and Papalazarou, Mr Vasileios and Falcone, Dr Mattia and Huerta Uribe, Mr Alejandro and Maddocks, Professor Oliver and Shanks, Dr Emma |
| Authors: | Papalazarou, V., Newman, A. C., Huerta-Uribe, A., Legrave, N. M., Falcone, M., Zhang, T., McGarry, L., Athineos, D., Shanks, E., Blyth, K., Vousden, K. H., and Maddocks, O. D. K. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Nature Metabolism |
| Publisher: | Nature Research |
| ISSN: | 2522-5812 |
| ISSN (Online): | 2522-5812 |
| Published Online: | 08 December 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Nature Metabolism 5(12): 2148-2168 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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