Cargando…
Metabolic plasticity in CLL: adaptation to the hypoxic niche
Metabolic transformation in cancer is increasingly well understood. However, little is known about the metabolic responses of cancer cells that permit their survival in different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism in living primary chron...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705428/ https://www.ncbi.nlm.nih.gov/pubmed/26202928 http://dx.doi.org/10.1038/leu.2015.187 |
_version_ | 1782409011475251200 |
---|---|
author | Koczula, K M Ludwig, C Hayden, R Cronin, L Pratt, G Parry, H Tennant, D Drayson, M Bunce, C M Khanim, F L Günther, U L |
author_facet | Koczula, K M Ludwig, C Hayden, R Cronin, L Pratt, G Parry, H Tennant, D Drayson, M Bunce, C M Khanim, F L Günther, U L |
author_sort | Koczula, K M |
collection | PubMed |
description | Metabolic transformation in cancer is increasingly well understood. However, little is known about the metabolic responses of cancer cells that permit their survival in different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism in living primary chronic lymphoid leukemia (CLL) cells and to interrogate their real-time metabolic responses to hypoxia. Our studies demonstrate considerable metabolic plasticity in CLL cells. Despite being in oxygenated blood, circulating CLL cells are primed for hypoxia as measured by constitutively low level hypoxia-inducible factor (HIF-1α) activity and modest lactate production from glycolysis. Upon entry to hypoxia we observed rapid upregulation of metabolic rates. CLL cells that had adapted to hypoxia returned to the ‘primed' state when re-oxygenated and again showed the same adaptive response upon secondary exposure to hypoxia. We also observed HIF-1α independent differential utilization of pyruvate in oxygenated and hypoxic conditions. When oxygenated, CLL cells released pyruvate, but in hypoxia imported pyruvate to protect against hypoxia-associated oxidative stress. Finally, we identified a marked association of slower resting glucose and glutamine consumption, and lower alanine and lactate production with Binet A0 stage samples indicating that CLL may be divided into tumors with higher and lower metabolic states that reflect disease stage. |
format | Online Article Text |
id | pubmed-4705428 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47054282016-01-25 Metabolic plasticity in CLL: adaptation to the hypoxic niche Koczula, K M Ludwig, C Hayden, R Cronin, L Pratt, G Parry, H Tennant, D Drayson, M Bunce, C M Khanim, F L Günther, U L Leukemia Original Article Metabolic transformation in cancer is increasingly well understood. However, little is known about the metabolic responses of cancer cells that permit their survival in different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism in living primary chronic lymphoid leukemia (CLL) cells and to interrogate their real-time metabolic responses to hypoxia. Our studies demonstrate considerable metabolic plasticity in CLL cells. Despite being in oxygenated blood, circulating CLL cells are primed for hypoxia as measured by constitutively low level hypoxia-inducible factor (HIF-1α) activity and modest lactate production from glycolysis. Upon entry to hypoxia we observed rapid upregulation of metabolic rates. CLL cells that had adapted to hypoxia returned to the ‘primed' state when re-oxygenated and again showed the same adaptive response upon secondary exposure to hypoxia. We also observed HIF-1α independent differential utilization of pyruvate in oxygenated and hypoxic conditions. When oxygenated, CLL cells released pyruvate, but in hypoxia imported pyruvate to protect against hypoxia-associated oxidative stress. Finally, we identified a marked association of slower resting glucose and glutamine consumption, and lower alanine and lactate production with Binet A0 stage samples indicating that CLL may be divided into tumors with higher and lower metabolic states that reflect disease stage. Nature Publishing Group 2016-01 2015-09-04 /pmc/articles/PMC4705428/ /pubmed/26202928 http://dx.doi.org/10.1038/leu.2015.187 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Koczula, K M Ludwig, C Hayden, R Cronin, L Pratt, G Parry, H Tennant, D Drayson, M Bunce, C M Khanim, F L Günther, U L Metabolic plasticity in CLL: adaptation to the hypoxic niche |
title | Metabolic plasticity in CLL: adaptation to the hypoxic niche |
title_full | Metabolic plasticity in CLL: adaptation to the hypoxic niche |
title_fullStr | Metabolic plasticity in CLL: adaptation to the hypoxic niche |
title_full_unstemmed | Metabolic plasticity in CLL: adaptation to the hypoxic niche |
title_short | Metabolic plasticity in CLL: adaptation to the hypoxic niche |
title_sort | metabolic plasticity in cll: adaptation to the hypoxic niche |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705428/ https://www.ncbi.nlm.nih.gov/pubmed/26202928 http://dx.doi.org/10.1038/leu.2015.187 |
work_keys_str_mv | AT koczulakm metabolicplasticityinclladaptationtothehypoxicniche AT ludwigc metabolicplasticityinclladaptationtothehypoxicniche AT haydenr metabolicplasticityinclladaptationtothehypoxicniche AT croninl metabolicplasticityinclladaptationtothehypoxicniche AT prattg metabolicplasticityinclladaptationtothehypoxicniche AT parryh metabolicplasticityinclladaptationtothehypoxicniche AT tennantd metabolicplasticityinclladaptationtothehypoxicniche AT draysonm metabolicplasticityinclladaptationtothehypoxicniche AT buncecm metabolicplasticityinclladaptationtothehypoxicniche AT khanimfl metabolicplasticityinclladaptationtothehypoxicniche AT guntherul metabolicplasticityinclladaptationtothehypoxicniche |