Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-22640-y
Keywords
-
Categories
Funding
- Gillson Longenbaugh Foundation
- National Cancer Institute [R21 CA178450]
- National Institutes of Health Cancer Center Support Grant [P30 CA016672]
- Cancer Prevention and Research Institute of Texas [RP170366]
- E.L. Weigand Foundation
- James B. and Lois R. Archer Foundation
- CPRIT Core Facility Support Award [RP170005]
- NCI Cancer Center Support Grant [P30CA125123]
- Dan L. Duncan Cancer Center (DLDCC)
- Alkek Center for Molecular Discovery
- American Cancer Society [127430-RSG-15-105-01-CNE]
- NIH [U01CA167234, DK56338, CA125123]
- CPRIT [RP150578, RP170719]
- Dan L. Duncan Comprehensive Cancer Center
- John S. Dunn Gulf Coast Consortium for Chemical Genomics
Ask authors/readers for more resources
Cisplatin is commonly utilized in the treatment of solid tumors. Its mechanism of action is complex and multiple mechanisms of resistance have been described. We sought to determine the impact of cisplatin-generated oxidative stress on head and neck squamous cell carcinoma (HNSCC) proliferation, survival and metabolic activity in order to identify a potential metabolic signature associated with cisplatin response. DNA-bound cisplatin represents a small fraction of total intra-cellular cisplatin but generates a robust oxidative stress response. Neutralization of oxidative stress reverses cisplatin toxicity independent of the mechanism of cell death and TP53 mutational status. Cisplatin-induced oxidative stress triggers rapid shifts in carbon flux in 3 commonly utilized catabolic pathways: glycolysis, pentose phosphate pathway and citric acid cycle. Among these metabolic shifts, decreased flux from pyruvate into lactate is the only metabolic effect consistently observed across multiple HNSCC cell lines of varying genomic backgrounds and may reflect differential cisplatin sensitivity. Oxidative stress is a critical component of cisplatin cytotoxicity in HNSCC and is reflected in acute changes in carbon flux from pyruvate into lactate. This suggests that lactate may contribute to a metabolic signature of acute cisplatin toxicity, and could prove useful in optimizing cisplatin-based treatment regimens in HNSCC.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available