@article{60ca728dec294d0ead51c6b4e6795168,
title = "Acquisition of cisplatin resistance shifts head and neck squamous cell carcinoma metabolism toward neutralization of oxidative stress",
abstract = "Background: Cisplatin (CDDP) is commonly utilized in the treatment of advanced solid tumors including head and neck squamous cell carcinoma (HNSCC). Cisplatin response remains highly variable among individual tumors and development of cisplatin resistance is common. We hypothesized that development of cisplatin resistance is partially driven by metabolic reprogramming. Methods: Using a pre-clinical HNSCC model and an integrated approach to steady state metabolomics, metabolic flux and gene expression data we characterized the interaction between cisplatin resistance and metabolic reprogramming. Results: Cisplatin toxicity in HNSCC was driven by generation of intra-cellular oxidative stress. This was validated by demonstrating that acquisition of cisplatin resistance generates cross-resistance to ferroptosis agonists despite the fact that cisplatin itself does not trigger ferroptosis. Acquisition of cisplatin resistance dysregulated the expression of genes involved in amino acid, fatty acid metabolism and central carbon catabolic pathways, enhanced glucose catabolism and serine synthesis. Acute cisplatin exposure increased intra-tumoral levels of S-methyl-5-thiadenosine (MTA) precursors and metabotoxins indicative of generalized oxidative stress. Conclusions: Acquisition of cisplatin resistance is linked to metabolic recovery from oxidative stress. Although this portends poor effectiveness for directed metabolic targeting, it supports the potential for biomarker development of cisplatin effectiveness using an integrated approach.",
keywords = "Amino acid, Cisplatin, Fatty acid, Ferroptosis, Head and neck cancer, Oxidative stress",
author = "Wangjie Yu and Yunyun Chen and Nagireddy Putluri and Cristian Coarfa and Robertson, {Matthew J.} and Vasanta Putluri and Fabio Stossi and Julien Dubrulle and Mancini, {Michael A.} and Pang, {Jonathan C.} and Trung Nguyen and Dodge Baluya and Myers, {Jeffrey N.} and Lai, {Stephen Y.} and Sandulache, {Vlad C.}",
note = "Funding Information: Funding: V.C.S. and W.Y. receive support from the Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, the Mike Hogg Fund and the Gillson Longenbaugh Foundation. V.C.S. is supported by NIDCR R03DE028858, a Translational Innovator Award from the American Head and Neck Society and the American Academy of Otolaryngology Head and Neck Surgery Foundation. V.C.S., S.Y.L. and Y.C. are supported by CPRIT RP170366. F.S., J.D. and M.A.M. are supported by the Integrated Microscopy Core at Baylor College of Medicine with funding from NIH (DK56338 and CA125123), CPRIT (RP150578, RP170719), the Dan L. Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. This project was supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine with funding from the NIH NCI grant (P30CA125123) and the expert assistance of Dr. Lisa D. White, Ph.D., Md Habibul Islam and Daniel C. Kraushaar, Ph.D. CIRC receives support from the E.L. Wiegand Foundation and James B. and Lois R. Archer Foundation. C.C. and M.J.R. are supported by CPRIT Core Facility RP170005, NIH P30 shared resource grant CA125123 and NIEHS P30 Center grant 1P30ES030285-01. V.P. and N.P. are supported by the CPRIT Core Facility Support Award RP170005 “Proteomic and Metabolomic Core Facility,” NCI Cancer Center Support Grant P30CA125123, intramural funds from the Dan L. Duncan Cancer Center (DLDCC) and intramural funds from the Alkek Center for Molecular Discovery. N.P. is also supported by the American Cancer Society (award 127430-RSG-15-105-01-CNE), NIH/NCI R01CA220297 and NIH/NCI R01CA216426. The Baylor College of Medicine Metabolomics Core is a designated Agilent Technologies Center for Excellence in Mass Spectrometry. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: V.C.S. and W.Y. receive support from the Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, the Mike Hogg Fund and the Gillson Longenbaugh Foundation. V.C.S. is supported by NIDCR R03DE028858, a Translational Innovator Award from the American Head and Neck Society and the American Academy of Otolaryngology Head and Neck Surgery Foundation. V.C.S., S.Y.L. and Y.C. are supported by CPRIT RP170366. F.S., J.D. and M.A.M. are supported by the Integrated Microscopy Core at Baylor College of Medicine with funding from NIH (DK56338 and CA125123), CPRIT (RP150578, RP170719), the Dan L. Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. This project was supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine with funding from the NIH NCI grant (P30CA125123) and the expert assistance of Dr. Lisa D. White, Ph.D., Md Habibul Islam and Daniel C. Kraushaar, Ph.D. CIRC receives support from the E.L. Wiegand Foundation and James B. and Lois R. Archer Foundation. C.C. and M.J.R. are supported by CPRIT Core Facility RP170005, NIH P30 shared resource grant CA125123 and NIEHS P30 Center grant 1P30ES030285-01. V.P. and N.P. are supported by the CPRIT Core Facility Support Award RP170005 ?Proteomic and Metabolomic Core Facility,? NCI Cancer Center Support Grant P30CA125123, intramural funds from the Dan L. Duncan Cancer Center (DLDCC) and intramural funds from the Alkek Center for Molecular Discovery. N.P. is also supported by the American Cancer Society (award 127430-RSG-15-105-01-CNE), NIH/NCI R01CA220297 and NIH/NCI R01CA216426. The Baylor College of Medicine Metabolomics Core is a designated Agilent Technologies Center for Excellence in Mass Spectrometry. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = jun,
doi = "10.3390/cancers12061670",
language = "English (US)",
volume = "12",
pages = "1--16",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "6",
}