Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress
<i>Background</i>: 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 hypothesize...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/6/1670 |
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| author | Wangjie Yu Yunyun Chen Nagireddy Putluri Cristian Coarfa Matthew J. Robertson Vasanta Putluri Fabio Stossi Julien Dubrulle Michael A. Mancini Jonathan C. Pang Trung Nguyen Dodge Baluya Jeffrey N. Myers Stephen Y. Lai Vlad C. Sandulache |
| author_facet | Wangjie Yu Yunyun Chen Nagireddy Putluri Cristian Coarfa Matthew J. Robertson Vasanta Putluri Fabio Stossi Julien Dubrulle Michael A. Mancini Jonathan C. Pang Trung Nguyen Dodge Baluya Jeffrey N. Myers Stephen Y. Lai Vlad C. Sandulache |
| author_sort | Wangjie Yu |
| collection | DOAJ |
| description | <i>Background</i>: 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. <i>Methods</i>: 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. <i>Results</i>: 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. <i>Conclusions:</i> 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. |
| first_indexed | 2024-03-10T18:55:45Z |
| format | Article |
| id | doaj.art-d743c9a367cb4ce993ed8b6bb46eb28a |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T18:55:45Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d743c9a367cb4ce993ed8b6bb46eb28a2023-11-20T04:47:10ZengMDPI AGCancers2072-66942020-06-01126167010.3390/cancers12061670Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative StressWangjie Yu0Yunyun Chen1Nagireddy Putluri2Cristian Coarfa3Matthew J. Robertson4Vasanta Putluri5Fabio Stossi6Julien Dubrulle7Michael A. Mancini8Jonathan C. Pang9Trung Nguyen10Dodge Baluya11Jeffrey N. Myers12Stephen Y. Lai13Vlad C. Sandulache14Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USADepartment of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USADepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USAAdvanced Technology Core, Dan Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USAAdvanced Technology Core, Dan Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USADepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USADepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USABobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USABobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USAChemical Imaging Research Center (CIRC), University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USABobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USA<i>Background</i>: 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. <i>Methods</i>: 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. <i>Results</i>: 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. <i>Conclusions:</i> 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.https://www.mdpi.com/2072-6694/12/6/1670cisplatinhead and neck cancerfatty acidferroptosisamino acidoxidative stress |
| spellingShingle | Wangjie Yu Yunyun Chen Nagireddy Putluri Cristian Coarfa Matthew J. Robertson Vasanta Putluri Fabio Stossi Julien Dubrulle Michael A. Mancini Jonathan C. Pang Trung Nguyen Dodge Baluya Jeffrey N. Myers Stephen Y. Lai Vlad C. Sandulache Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress Cancers cisplatin head and neck cancer fatty acid ferroptosis amino acid oxidative stress |
| title | Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress |
| title_full | Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress |
| title_fullStr | Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress |
| title_full_unstemmed | Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress |
| title_short | Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress |
| title_sort | acquisition of cisplatin resistance shifts head and neck squamous cell carcinoma metabolism toward neutralization of oxidative stress |
| topic | cisplatin head and neck cancer fatty acid ferroptosis amino acid oxidative stress |
| url | https://www.mdpi.com/2072-6694/12/6/1670 |
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