Exploring Lipid Reprogramming in Hypoxic Cancer Cells: Targeting Lipid Metabolism for Therapeutic Innovation
DOI:
https://doi.org/10.58445/rars.2393Keywords:
Hypoxia, Lipid Metabolism, Cancer Cell Adaptation, Fatty Acid Synthase (FASN), Acetyl-CoA Carboxylase (ACC), Therapeutic TargetingAbstract
The rapid proliferation of cancer cells results in hypoxia (low oxygen levels). They undergo metabolic reprogramming, including lipid metabolism to survive and grow in response to hypoxia. This study investigates the specific enzymes and processes that occur in response to low oxygen levels, including fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC), which are upregulated in response to hypoxia. In addition, this study indicates the accumulation of lipid droplets under hypoxia. The role of hypoxia-inducible factors (HIFs) under hypoxia is investigated. Gene expression analysis, metabolite profiling, and enzyme activity assays are employed to identify the changes in lipid metabolism that facilitate tumor progression under hypoxia and vivo techniques by using mice as models. The findings provide the development of lipid-targeting therapies that may enhance the current cancer treatment by targeting the upregulated enzymes because they help cancer cells to proliferate and survive in the case of low-oxygen, therefore targeting these enzymes may significantly slow tumor progression, reduce proliferation, and inhibit metastasis.
References
Ackerman, D., & Simon, M. C. (2014). Hypoxia, lipids, and cancer: Surviving the harsh tumor microenvironment. *Trends in Cell Biology, 24*(8), 472–478. https://doi.org/10.1016/j.tcb.2014.06.001
Calabrese, B. (2019). Experimental platforms for extracting biological data: Mass spectrometry, microarray, next-generation sequencing. In *Elsevier eBooks* (pp. 126–129). https://doi.org/10.1016/b978-0-12-809633-8.20412-3
Chan, D. A., & Giaccia, A. J. (2010). PHD2 in tumour angiogenesis. *British Journal of Cancer, 103*(1), 1–5. https://doi.org/10.1038/sj.bjc.6605682
Enzyme Activity Assays - Creative Biolabs. (n.d.). https://www.creative-biolabs.com/enzyme-activity-assays.html
Furuta, E., Pai, S. K., Zhan, R., Bandyopadhyay, S., Watabe, M., Mo, Y., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Kamada, S., Saito, K., Iiizumi, M., Liu, W., Ericsson, J., & Watabe, K. (2008). Fatty acid synthase gene is up-regulated by hypoxia via activation of AKT and sterol regulatory element binding protein-1. *Cancer Research, 68*(4), 1003–1011. https://doi.org/10.1158/0008-5472.can-07-2489
Gao, X., Lin, S., Ren, F., Li, J. T., Chen, J. J., Yao, C. B., Yang, H. B., Jiang, S. X., Yan, G. Q., Wang, D., Wang, Y., Liu, Y., Cai, Z., Xu, Y. Y., Chen, J., Yu, W., Yang, P. Y., & Lei, Q. Y. (2016). Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. *Nature Communications, 7*(1). https://doi.org/10.1038/ncomms11960
Gao, X., Lin, S., Ren, F., Li, J. T., Chen, J. J., Yao, C. B., Yang, H. B., Jiang, S. X., Yan, G. Q., Wang, D., Wang, Y., Liu, Y., Cai, Z., Xu, Y. Y., Chen, J., Yu, W., Yang, P. Y., & Lei, Q. Y. (2023). Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. *Nature Communications, 14*(1). https://doi.org/10.1038/s41467-023-41782-w
Gilreath, C., Boerma, M., Qin, Z., Hudson, M. K., & Wang, S. (2021). The hypoxic microenvironment of breast cancer cells promotes resistance in radiation therapy. *Frontiers in Oncology, 10*. https://doi.org/10.3389/fonc.2020.629422
Heck-Swain, K., & Koeppen, M. (2023). The intriguing role of hypoxia-inducible factor in myocardial ischemia and reperfusion: A comprehensive review. *Journal of Cardiovascular Development and Disease, 10*(5), 215. https://doi.org/10.3390/jcdd10050215
Hirota, K., & Semenza, G. L. (2006). Regulation of angiogenesis by hypoxia-inducible factor 1. *Critical Reviews in Oncology/Hematology, 59*(1), 15–26. https://doi.org/10.1016/j.critrevonc.2005.12.003
Infantino, V., Santarsiero, A., Convertini, P., Todisco, S., & Iacobazzi, V. (2021). Cancer cell metabolism in hypoxia: Role of HIF-1 as key regulator and therapeutic target. *International Journal of Molecular Sciences, 22*(11), 5703. https://doi.org/10.3390/ijms22115703
Khuda-Bukhsh, A. R., Das, J., & Samadder, A. (2023). Mice as experimental models for cancer research. In *Handbook of Animal Models and Its Uses in Cancer Research* (pp. 87–109). https://doi.org/10.1007/978-981-19-3824-5_5
Krock, B. L., Skuli, N., & Simon, M. C. (2011). Hypoxia-induced angiogenesis: Good and evil. *Genes & Cancer, 2*(12), 1117–1133. https://doi.org/10.1177/1947601911423654
Lee, M. (2015). Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication. *World Journal of Biological Chemistry, 6*(3), 148. https://doi.org/10.4331/wjbc.v6.i3.148
Li, Y., Zhao, L., & Li, X. (2021). Hypoxia and the tumor microenvironment. *Technology in Cancer Research & Treatment, 20*, 153303382110363. https://doi.org/10.1177/15330338211036304
McKeown, S. R. (2014). Defining normoxia, physoxia, and hypoxia in tumours—implications for treatment response. *British Journal of Radiology, 87*(1035), 20130676. https://doi.org/10.1259/bjr.20130676
Mounier, C., Bouraoui, L., & Rassart, E. (2014). Lipogenesis in cancer progression (Review). *International Journal of Oncology, 45*(2), 485–492. https://doi.org/10.3892/ijo.2014.2441
Munir, R., Lisec, J., Swinnen, J. V., & Zaidi, N. (2019). Lipid metabolism in cancer cells under metabolic stress. *British Journal of Cancer, 120*(12), 1090–1098. https://doi.org/10.1038/s41416-019-0451-4
Mylonis, I., Simos, G., & Paraskeva, E. (2019). Hypoxia-inducible factors and the regulation of lipid metabolism. *Cells, 8*(3), 214. https://doi.org/10.3390/cells8030214
Peck, B., & Schulze, A. (2016). Lipid desaturation—The next step in targeting lipogenesis in cancer? *FEBS Journal, 283*(15), 2767–2778. https://doi.org/10.1111/febs.13681
Pavlides, S., Whitaker-Menezes, D., Castello-Cros, R., Flomenberg, N., Witkiewicz, A. K., Frank, P. G., Casimiro, M. C., Wang, C., Fortina, P., Addya, S., Pestell, R. G., Martinez-Outschoorn, U. E., Sotgia, F., & Lisanti, M. P. (2009). The reverse Warburg effect: Aerobic glycolysis in cancer-associated fibroblasts and the tumor stroma. *Cell Cycle, 8*(23), 3984–4001. https://doi.org/10.4161/cc.8.23.10238
Quantitative PCR Basics. (n.d.). https://www.sigmaaldrich.com/EG/en/technical-documents/technical-article/genomics/qpcr/quantitative-pcr#mrna
Schiliro, C., & Firestein, B. L. (2021). Mechanisms of metabolic reprogramming in cancer cells supporting enhanced growth and proliferation. *Cells, 10*(5), 1056. https://doi.org/10.3390/cells10051056
Seo, J., Yun, J., Kim, S. J., & Chun, Y. (2022). Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment. *Pflügers Archiv - European Journal of Physiology, 474*(6), 591–601. https://doi.org/10.1007/s00424-022-02683-x
Wang, D., Buja, L., & McMillin, J. B. (1996). Acetyl coenzyme A carboxylase activity in neonatal rat cardiac myocytes in culture: Citrate dependence and effects of hypoxia. *Archives of Biochemistry and Biophysics, 325*(2
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