Display options
Cite
Varshavi D, Varshavi D, McCarthy N, et al. Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines. Metabolomics. 2021;17(12):104doi: 10.1007/s11306-021-01852-w.
Varshavi, D., Varshavi, D., McCarthy, N., Veselkov, K., Keun, H. C., & Everett, J. R. (2021). Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines. Metabolomics : Official journal of the Metabolomic Society, 17(12), 104. https://doi.org/10.1007/s11306-021-01852-w
Varshavi, Dorna, et al. "Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines." Metabolomics : Official journal of the Metabolomic Society vol. 17,12 (2021): 104. doi: https://doi.org/10.1007/s11306-021-01852-w
Varshavi D, Varshavi D, McCarthy N, Veselkov K, Keun HC, Everett JR. Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines. Metabolomics. 2021 Nov 25;17(12):104. doi: 10.1007/s11306-021-01852-w. PMID: 34822010; PMCID: PMC8616861.
Copy Download .nbib Format: NLM
Share it on

Metabolomics. 2021 Nov 25;17(12):104. doi: 10.1007/s11306-021-01852-w.

Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines.

Metabolomics : Official journal of the Metabolomic Society

Dorna Varshavi, Dorsa Varshavi, Nicola McCarthy, Kirill Veselkov, Hector C Keun, Jeremy R Everett

Affiliations

  1. Medway Metabonomics Research Group, University of Greenwich, Chatham Maritime, ME4 4TB, Kent, UK.
  2. Department of Biological Sciences, University of Alberta, 116 Street & 85 Ave, Edmonton, AB, T6G 2R3, Canada.
  3. Horizon Discovery Ltd., Cambridge Research Park, 8100 Beach Dr, Waterbeach, Cambridge, CB25 9TL, UK.
  4. Milner Therapeutics Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge, CB2 0AW, UK.
  5. Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, SW7 2AZ, UK.
  6. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 ONN, UK.
  7. Medway Metabonomics Research Group, University of Greenwich, Chatham Maritime, ME4 4TB, Kent, UK. [email protected].

PMID: 34822010 PMCID: PMC8616861 DOI: 10.1007/s11306-021-01852-w

Abstract

INTRODUCTION: KRAS was one of the earliest human oncogenes to be described and is one of the most commonly mutated genes in different human cancers, including colorectal cancer. Despite KRAS mutants being known driver mutations, KRAS has proved difficult to target therapeutically, necessitating a comprehensive understanding of the molecular mechanisms underlying KRAS-driven cellular transformation.

OBJECTIVES: To investigate the metabolic signatures associated with single copy mutant KRAS in isogenic human colorectal cancer cells and to determine what metabolic pathways are affected.

METHODS: Using NMR-based metabonomics, we compared wildtype (WT)-KRAS and mutant KRAS effects on cancer cell metabolism using metabolic profiling of the parental KRAS

RESULTS: Mutation in the KRAS oncogene leads to a general metabolic remodelling to sustain growth and counter stress, including alterations in the metabolism of amino acids and enhanced glutathione biosynthesis. Additionally, we show that KRAS

CONCLUSIONS: Our study showed the effect of a single point mutation in one KRAS allele and KRAS allele loss in an isogenic genetic background, hence avoiding confounding genetic factors. Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS.

© 2021. The Author(s).

Keywords: Cells; Colorectal cancer; HCT116; KRAS; Metabolic profiling; Metabolomics; Metabonomics; Mutations; NMR

References

  1. J Biol Chem. 2013 Jan 25;288(4):2403-13 - PubMed
  2. Br J Cancer Suppl. 1987 Jun;8:96-104 - PubMed
  3. Chem Biol Interact. 1998 Apr 24;111-112:213-24 - PubMed
  4. Nat Genet. 2001 Sep;29(1):25-33 - PubMed
  5. Mol Cell. 2014 Oct 23;56(2):205-218 - PubMed
  6. Eur J Clin Invest. 2015 Jan;45 Suppl 1:37-43 - PubMed
  7. Am J Pathol. 2002 Jun;160(6):2169-80 - PubMed
  8. Neoplasia. 2016 Nov;18(11):654-665 - PubMed
  9. Nat Rev Cancer. 2016 Oct;16(10):650-62 - PubMed
  10. Pharmacol Ther. 1991;51(2):155-94 - PubMed
  11. Oncotarget. 2016 Jul 19;7(29):46717-46733 - PubMed
  12. Trends Biochem Sci. 2014 Apr;39(4):191-8 - PubMed
  13. Clin Cancer Res. 2009 Jan 15;15(2):431-40 - PubMed
  14. Int J Mol Sci. 2012 Sep 25;13(10):12153-68 - PubMed
  15. Comput Struct Biotechnol J. 2015 Jan 27;13:131-44 - PubMed
  16. Nature. 2013 Jan 24;493(7433):542-6 - PubMed
  17. Cancer Cell. 2005 Jan;7(1):77-85 - PubMed
  18. Metabolomics. 2007 Sep;3(3):211-221 - PubMed
  19. Cancer Res. 1984 Oct;44(10):4224-32 - PubMed
  20. Nature. 2012 Nov 15;491(7424):364-73 - PubMed
  21. Cancer Metab. 2015 Jan 25;3(1):1 - PubMed
  22. Science. 2012 May 25;336(6084):1040-4 - PubMed
  23. Mol Cell Oncol. 2014 Oct 29;1(3):e963452 - PubMed
  24. Nat Med. 1995 Jan;1(1):84-8 - PubMed
  25. Metabolomics. 2020 Apr 16;16(4):51 - PubMed
  26. Cancer Cell. 2015 Jan 12;27(1):57-71 - PubMed
  27. Int J Cancer. 2012 Oct 15;131(8):1810-7 - PubMed
  28. PLoS One. 2012;7(9):e45190 - PubMed
  29. Mol Cell. 2014 Nov 6;56(3):414-424 - PubMed
  30. Anal Bioanal Chem. 2011 Jan;399(3):1127-39 - PubMed
  31. Cancers (Basel). 2010 Mar 26;2(2):274-304 - PubMed
  32. Nature. 2016 Mar 3;531(7592):110-3 - PubMed
  33. Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8983-8 - PubMed
  34. Cell Metab. 2006 Mar;3(3):187-97 - PubMed
  35. Mutat Res. 2009 Mar 31;674(1-2):3-22 - PubMed
  36. Cancer Metab. 2014 Dec 11;2:23 - PubMed
  37. Crit Rev Clin Lab Sci. 2006;43(2):143-81 - PubMed
  38. Front Pharmacol. 2014 Aug 26;5:196 - PubMed
  39. Comput Struct Biotechnol J. 2016 Mar 09;14:135-53 - PubMed
  40. Trends Pharmacol Sci. 2019 Oct;40(10):763-773 - PubMed
  41. Hepatology. 2002 Jan;35(1):74-81 - PubMed
  42. Cell Cycle. 2013 Jul 1;12(13):1987-8 - PubMed
  43. J Med Life. 2014 Oct-Dec;7(4):581-7 - PubMed
  44. J Carcinog. 2013 Jun 18;12:9 - PubMed
  45. Front Mol Biosci. 2018 Apr 09;5:28 - PubMed
  46. Nature. 2013 Apr 4;496(7443):101-5 - PubMed
  47. Nat Commun. 2018 Jan 2;9(1):38 - PubMed
  48. Semin Cell Dev Biol. 2015 Jul;43:22-32 - PubMed
  49. Cell Metab. 2006 Mar;3(3):177-85 - PubMed
  50. Nature. 2011 Aug 18;476(7360):346-50 - PubMed
  51. Science. 2016 Sep 9;353(6304):1161-5 - PubMed
  52. Cell Rep. 2014 May 22;7(4):1248-58 - PubMed
  53. Oncogene. 2013 Aug 22;32(34):4028-33 - PubMed
  54. Int J Exp Pathol. 2014 Feb;95(1):8-15 - PubMed
  55. Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1216-21 - PubMed

Publication Types