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Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress

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Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USA
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Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
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Advanced Technology Core, Dan Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
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GCC Center for Advanced Microscopy and Image Informatics, Houston, TX 77030, USA
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Chemical Imaging Research Center (CIRC), University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1670; https://doi.org/10.3390/cancers12061670
Received: 30 May 2020 / Revised: 18 June 2020 / Accepted: 20 June 2020 / Published: 24 June 2020
(This article belongs to the Section Molecular Cancer Biology)
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. View Full-Text
Keywords: cisplatin; head and neck cancer; fatty acid; ferroptosis; amino acid; oxidative stress cisplatin; head and neck cancer; fatty acid; ferroptosis; amino acid; oxidative stress
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Yu, W.; Chen, Y.; Putluri, N.; Coarfa, C.; Robertson, M.J.; Putluri, V.; Stossi, F.; Dubrulle, J.; Mancini, M.A.; Pang, J.C.; Nguyen, T.; Baluya, D.; Myers, J.N.; Lai, S.Y.; Sandulache, V.C. Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress. Cancers 2020, 12, 1670.

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