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Addie RD, de Jong Y, Alberti G, et al. Exploration of the chondrosarcoma metabolome; the mTOR pathway as an important pro-survival pathway. J Bone Oncol. 2019;15:100222doi: 10.1016/j.jbo.2019.100222.
Addie, R. D., de Jong, Y., Alberti, G., Kruisselbrink, A. B., Que, I., Baelde, H., & Bovée, J. V. M. G. (2019). Exploration of the chondrosarcoma metabolome; the mTOR pathway as an important pro-survival pathway. Journal of bone oncology, 15100222. https://doi.org/10.1016/j.jbo.2019.100222
Addie, Ruben D, et al. "Exploration of the chondrosarcoma metabolome; the mTOR pathway as an important pro-survival pathway." Journal of bone oncology vol. 15 (2019): 100222. doi: https://doi.org/10.1016/j.jbo.2019.100222
Addie RD, de Jong Y, Alberti G, Kruisselbrink AB, Que I, Baelde H, Bovée JVMG. Exploration of the chondrosarcoma metabolome; the mTOR pathway as an important pro-survival pathway. J Bone Oncol. 2019 Jan 29;15:100222. doi: 10.1016/j.jbo.2019.100222. eCollection 2019 Apr. PMID: 30766792; PMCID: PMC6360255.
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J Bone Oncol. 2019 Jan 29;15:100222. doi: 10.1016/j.jbo.2019.100222. eCollection 2019 Apr.

Exploration of the chondrosarcoma metabolome; the mTOR pathway as an important pro-survival pathway.

Journal of bone oncology

Ruben D Addie, Yvonne de Jong, Gaia Alberti, Alwine B Kruisselbrink, Ivo Que, Hans Baelde, Judith V M G Bovée

Affiliations

  1. Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.
  2. Department of Radiology, Leiden University Medical Centre, Leiden, the Netherlands.

PMID: 30766792 PMCID: PMC6360255 DOI: 10.1016/j.jbo.2019.100222

Abstract

BACKGROUND: Chondrosarcomas are malignant cartilage-producing tumors showing mutations and changes in gene expression in metabolism related genes. In this study, we aimed to explore the metabolome and identify targetable metabolic vulnerabilities in chondrosarcoma.

METHODS: A custom-designed metabolic compound screen containing 39 compounds targeting different metabolic pathways was performed in chondrosarcoma cell lines JJ012, SW1353 and CH2879. Based on the anti-proliferative activity, six compounds were selected for validation using real-time metabolic profiling. Two selected compounds (rapamycin and sapanisertib) were further explored for their effect on viability, apoptosis and metabolic dependency, in normoxia and hypoxia.

RESULTS: Inhibitors of glutamine, glutathione, NAD synthesis and mTOR were effective in chondrosarcoma cells. Of the six compounds that were validated on the metabolic level, mTOR inhibitors rapamycin and sapanisertib showed the most consistent decrease in oxidative and glycolytic parameters. Chondrosarcoma cells were sensitive to mTORC1 inhibition using rapamycin. Inhibition of mTORC1 and mTORC2 using sapanisertib resulted in a dose-dependent decrease in viability in all chondrosarcoma cell lines. In addition, induction of apoptosis was observed in CH2879 after 24 h. Treatment of chondrosarcoma xenografts with sapanisertib slowed down tumor growth compared to control mice.

CONCLUSIONS: mTOR inhibition leads to a reduction of oxidative and glycolytic metabolism and decreased proliferation in chondrosarcoma cell lines. Although further research is needed, these findings suggest that mTOR inhibition might be a potential therapeutic option for patients with chondrosarcoma.

Keywords: ACT, Atypical cartilaginous tumor; BLI, Bioluminescence imaging; BSA, Bovine serum albumin; BSO, Buthionine sulfoximine; Chondrosarcoma; D2HG, d-2-Hydroxyglutarate; DMSO, Dimethyl sulfoxide; ECAR, Extracellular acidification rate; FBS, Fetal bovine serum; FCCP, Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FLI, Fluorescence imaging; HIF, Hypoxia-inducible factor; IDH, Isocitrate dehydrogenase; Metabolism; OCR, Oxygen consumption rate; ROS, Reactive oxygen species; Rapamycin; mCT, Micro computed tomography; mTOR, Mammalian target of rapamycin; mTOR, Sapanisertib; α-KG, α-ketoglutarate

References

  1. Clin Orthop Relat Res. 2000 Jul;(376):291-303 - PubMed
  2. Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S36-40 - PubMed
  3. Lab Invest. 2003 Jun;83(6):877-87 - PubMed
  4. J Orthop Res. 2004 Nov;22(6):1175-81 - PubMed
  5. J Pathol. 2005 Sep;207(1):61-71 - PubMed
  6. Ann Otol Rhinol Laryngol. 1990 Jan;99(1):74-9 - PubMed
  7. Cancer Res. 2009 Aug 1;69(15):6216-22 - PubMed
  8. Nature. 2009 Dec 10;462(7274):739-44 - PubMed
  9. Histopathology. 2010 Apr;56(5):641-51 - PubMed
  10. Science. 2010 Dec 3;330(6009):1340-4 - PubMed
  11. Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3270-5 - PubMed
  12. J Pathol. 2011 Jul;224(3):334-43 - PubMed
  13. Nat Genet. 2011 Nov 06;43(12):1256-61 - PubMed
  14. Histopathology. 2012 Jan;60(2):363-5 - PubMed
  15. PLoS One. 2012;7(6):e32458 - PubMed
  16. Cancer Chemother Pharmacol. 2012 Dec;70(6):855-60 - PubMed
  17. Clin Cancer Res. 2013 Jul 15;19(14):3796-807 - PubMed
  18. Cancer Discov. 2013 Jul;3(7):730-41 - PubMed
  19. Ann Oncol. 2013 Nov;24(11):2916-22 - PubMed
  20. Nat Rev Drug Discov. 2013 Nov;12(11):829-46 - PubMed
  21. Tumour Biol. 2014 Jul;35(7):7017-24 - PubMed
  22. Oncol Rep. 2014 Jun;31(6):2727-34 - PubMed
  23. Cancer. 2014 Oct 15;120(20):3159-64 - PubMed
  24. Genome Res. 2014 Sep;24(9):1411-20 - PubMed
  25. Virchows Arch. 2015 Jan;466(1):101-9 - PubMed
  26. Mol Cancer Ther. 2015 Feb;14(2):395-406 - PubMed
  27. Arch Pharm Res. 2015 Mar;38(3):338-45 - PubMed
  28. J Biol Chem. 2015 Mar 27;290(13):8348-59 - PubMed
  29. J Pathol. 2015 Jul;236(3):348-59 - PubMed
  30. Cell. 2015 Jul 30;162(3):540-51 - PubMed
  31. Cell. 2015 Jul 30;162(3):552-63 - PubMed
  32. Biochem Biophys Res Commun. 2015 Dec 4-11;468(1-2):255-61 - PubMed
  33. Drug Des Devel Ther. 2016 Feb 24;10:571-83 - PubMed
  34. J BUON. 2016 Jan-Feb;21(1):244-51 - PubMed
  35. Oncogenesis. 2016 May 09;5:e222 - PubMed
  36. Cell Death Dis. 2016 Jun 09;7(6):e2253 - PubMed
  37. Lab Invest. 2016 Oct;96(10):1128-37 - PubMed
  38. Cell. 2017 Mar 9;168(6):960-976 - PubMed
  39. Clin Sarcoma Res. 2017 May 4;7:8 - PubMed
  40. Metabolites. 2017 May 20;7(2): - PubMed
  41. J Hepatol. 2017 Dec;67(6):1194-1203 - PubMed
  42. Mol Cancer Res. 2017 Dec;15(12):1714-1721 - PubMed
  43. J Cell Biochem. 2018 Feb;119(2):2320-2332 - PubMed
  44. Br J Cancer. 2018 Apr;118(8):1074-1083 - PubMed
  45. Cancer. 1977 Aug;40(2):818-31 - PubMed
  46. Diagn Mol Pathol. 1998 Feb;7(1):51-6 - PubMed
  47. Cancer. 1998 Dec 1;83(11):2324-34 - PubMed

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