Regulation of tumor cell glycometabolism and tumor therapy_Journal of Biomedical Engineering

Authors：

LIU Ge ,  SONG Guanbin

College of Bioengineering, Chongqing University, Chongqing 400030, P.R.China;

Corresponding author：

Keywords：

tumor cells; tumor stem cells; glucometabolism; energy metabolism; tumor therapy

DOI：

10.7507/1001-5515.201812025

Video：

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Tumor cells have unique energy metabolism phenomena, namely high glucose absorption, aerobic glycolysis and high lactic acid production, which are characterized by down-regulation of related proteins involved in oxidative metabolism in tumor cells, and up-regulation of glucose transporters and monocarboxylate transporters. Studies have shown that drugs that target tumor cell glucose metabolism have the ability to selectively kill tumor cells, bringing new hope for tumor treatment. Tumor stem cells are considered to be the root cause of tumor recurrence, metastasis and poor prognosis, and their energy metabolism characteristics have not yet been agreed. Studies have shown that reversing the energy metabolism of tumor stem cells can increase their chemosensitivity. This article reviews recent studies on tumor and tumor stem cell glucose metabolism and the opportunities and challenges of tumor treatment through targeting glucose metabolism, which might provide new ideas and opportunities for clinical tumor therapy.

Citation： LIU Ge, SONG Guanbin. Regulation of tumor cell glycometabolism and tumor therapy. Journal of Biomedical Engineering, 2019, 36(4): 691-695. doi: 10.7507/1001-5515.201812025 Copy

1.	Bell W B. The metabolism of tumours. BMJ, 1927, 2(3474): 221-222.
2.	Warburg O. On the origin of cancer cells. Science, 1956, 123(3191): 309-314.
3.	Teslaa T, Teitell M A. Techniques to monitor glycolysis. Methods Enzymol, 2014, 542(98): 91-114.
4.	Cesi G, Walbrecq G, Zimmer A, et al. ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells. Mol Cancer, 2017, 16(1): 102.
5.	Bohn T, Rapp S, Luther N, et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol, 2018, 19(12): 1319-1329.
6.	Sekine H, Yamamoto M, Motohashi H. Tumors sweeten macrophages with acids. Nat Immunol, 2018, 19(12): 1281-1283.
7.	Xing F, Luan Y, Cai J, et al. The anti-Warburg effect elicited by the cAMP-PGC1α pathway drives differentiation of glioblastoma cells into astrocytes. Cell Rep, 2017, 18(2): 468-481.
8.	陈竺, 孙关林, 陈赛娟, 等. 全反式维A酸诱导分化治疗急性早幼粒细胞白血病的机制研究. 上海第二医科大学学报, 2002, 22(5): S1-S4.
9.	朱新锋. 全反式维甲酸诱导分化肝癌干细胞作用研究. 昆明: 昆明医科大学, 2016.
10.	Molinari F, Pin F, Gorini S A, et al. The mitochondrial metabolic reprogramming agent trimetazidine as an `exercise mimetic' in cachectic C26-bearing mice. J Cachexia Sarcopenia Muscle, 2017, 8(6): 954-973.
11.	LaGory E L, Wu C, Taniguchi C M, et al. Suppression of PGC-1α is critical for reprogramming oxidative metabolism in renal cell carcinoma. Cell Rep, 2015, 12(1): 116-127.
12.	Broecker-Preuss M, Becher-Boveleth N, Bockisch A, et al. Regulation of glucose uptake in lymphoma cell lines by c-MYC and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability. J Transl Med, 2017, 15(1): 158.
13.	Eun K, Ham S W, Kim H. Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. BMB Rep, 2017, 50(3): 117-125.
14.	Peng F, Wang J H, Fan W J, et al. Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. Oncogene, 2018, 37(8): 1062-1074.
15.	Pouyafar A, Heydarabad M Z, Zade J A, et al. Modulation of lipolysis and glycolysis pathways in cancer stem cells changed multipotentiality and differentiation capacity toward endothelial lineage. Cell Biosci, 2019, 9: 30.
16.	Cheng Y, Lu Y, Zhang D, et al. Metastatic cancer cells compensate for low energy supplies in hostile microenvironments with bioenergetic adaptation and metabolic reprogramming. Int J Oncol, 2018, 53(6): 2590-2604.
17.	Zhou Kai, Yao Yueliang, He Zhicheng, et al. VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells. Cell Death Dis, 2018, 9(10): 988.
18.	Gao Cuicui, Shen Yao, Jin Fang, et al. Cancer stem cells in small cell lung cancer cell line H446: higher dependency on oxidative phosphorylation and mitochondrial substrate-level phosphorylation than non-stem cancer cells. PLoS One, 2016, 11(5): e0154576.
19.	Farge T, Saland E, de Toni F, et al. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. Cancer Discov, 2017, 7(7): 716-735.
20.	De Luca A, Fiorillo M, Peiris-Pagès M, et al. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells. Oncotarget, 2015, 6(17): 14777-14795.
21.	李敏, 王红, 张斯亮, 等. 二甲双胍对甲状腺未分化癌细胞增殖和能量代谢的影响. 现代肿瘤医学, 2016, 24(11): 1694-1698.
22.	Sancho P, Burgos-Ramos E, Tavera A, et al. MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab, 2015, 22(4): 590-605.
23.	Zhang Haifeng, Wu Chengsheng, Alshareef A, et al. The PI3K/AKT/c-MYC axis promotes the acquisition of cancer stem-like features in esophageal squamous cell carcinoma. Stem Cells, 2016, 34(8): 2040-2051.
24.	Izumi D, Ishimoto T, Miyake K, et al. Colorectal cancer stem cells acquire chemoresistance through the upregulation of F-box/WD repeat-containing protein 7 and the consequent degradation of c-Myc. Stem Cells, 2017, 35(9): 2027-2036.
25.	孙警辉. 力、化学刺激对肝癌干细胞迁移, 分化行为的影响及其相关分子机理. 重庆: 重庆大学, 2016.
26.	Deng Dong, Xu Chao, Sun Pengcheng, et al. Crystal structure of the human glucose transporter GLUT1. Nature, 2014, 510(7503): 121-125.
27.	Guo Zhengyang, Jia Junqiao, Yao Mingjie, et al. Diacylglycerol kinase gamma predicts prognosis and functions as a tumor suppressor by negatively regulating glucose transporter 1 in hepatocellular carcinoma. Exp Cell Res, 2018, 373(1-2): 211-220.
28.	Wang Yaodong, Li Shengjiao, Liao Jianxing. Inhibition of glucose transporter 1(GLUT1) chemosensitized head and neck cancer cells to cisplatin. Technol Cancer Res Treat, 2013, 12(6): 525-535.
29.	Kurahara H, Maemura K, Mataki Y, et al. Significance of glucose transporter type 1(GLUT-1) expression in the therapeutic strategy for pancreatic ductal adenocarcinoma. Ann Surg Oncol, 2018, 25(5): 1432-1439.
30.	Yakisich J S, Azad N, Kaushik V, et al. The biguanides metformin and buformin in combination with 2-deoxy-glucose or WZB-117 inhibit the viability of highly resistant human lung cancer cells. Stem Cells Int, 2019: 6254269.
31.	Libby C J, ZHANG Sixue, Benavides G A, et al. Identification of compounds that decrease glioblastoma growth and glucose uptake in vitro. ACS Chem Biol, 2018, 13(8): 2048-2057.
32.	de Castro T B, Mota A L, Bordin-Junior N A, et al. Immunohistochemical expression of melatonin receptor MT1 and glucose transporter GLUT1 in human breast cancer. Anticancer Agents Med Chem, 2018, 18(15): 2110-2116.
33.	Wang Yu, Yun Yuyu, Wu Bo, et al. FOXM1 promotes reprogramming of glucose metabolism in epithelial ovarian cancer cells via activation of GLUT1 and HK2 transcription. Oncotarget, 2016, 7(30): 47985-47997.
34.	Wu Xueliang, Wang Likun, Yang Dongdong, et al. Effects of glut1 gene silencing on proliferation, differentiation, and apoptosis of colorectal cancer cells by targeting the TGF-β/PI3K-AKT-mTOR signaling pathway. J Cell Biochem, 2018, 119(2): 2356-2367.
35.	Halestrap A P, Price N T. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochemical Journal, 1999, 343(2): 281-299.
36.	Benjamin D, Robay D, Hindupur S K, et al. Dual inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD⁺ depletion in cancer cells. Cell Rep, 2018, 25(11): 3047-3058.
37.	Miranda-Goncalves V, Granja S, Martinho O, et al. Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas. Oncotarget, 2016, 7(29): 46335-46353.
38.	Romero-Cordoba S L, Rodriguez-Cuevas S A, Bautista-Pina V, et al. Loss of function of miR-342-3p results in MCT1 over-expression and contributes to oncogenic metabolic reprogramming in triple negative breast cancer. Sci Rep, 2018, 8(1): 12252.
39.	Takada T, Takata K, Ashihara E. Inhibition of monocarboxylate transporter 1 suppresses the proliferation of glioblastoma stem cells. Journal of Physiological Sciences, 2016, 66(5): 387-396.
40.	Kong S C, Nohr-Nielsen A, Zeeberg K A, et al. Monocarboxylate transporters MCT1 and MCT4 regulate migration and invasion of pancreatic ductal adenocarcinoma cells. Pancreas, 2016, 45(7): 1036-1047.
41.	Van Hée V F, Labar D, Dehon G, et al. Radiosynthesis and validation of (±)-[¹⁸F]-3-fluoro-2-hydroxypropionate ([¹⁸F]-FLac) as a PET tracer of lactate to monitor MCT1-dependent lactate uptake in tumors. Oncotarget, 2017, 8(15): 24415-24428.

1. Bell W B. The metabolism of tumours. BMJ, 1927, 2(3474): 221-222.
2. Warburg O. On the origin of cancer cells. Science, 1956, 123(3191): 309-314.
3. Teslaa T, Teitell M A. Techniques to monitor glycolysis. Methods Enzymol, 2014, 542(98): 91-114.
4. Cesi G, Walbrecq G, Zimmer A, et al. ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells. Mol Cancer, 2017, 16(1): 102.
5. Bohn T, Rapp S, Luther N, et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol, 2018, 19(12): 1319-1329.
6. Sekine H, Yamamoto M, Motohashi H. Tumors sweeten macrophages with acids. Nat Immunol, 2018, 19(12): 1281-1283.
7. Xing F, Luan Y, Cai J, et al. The anti-Warburg effect elicited by the cAMP-PGC1α pathway drives differentiation of glioblastoma cells into astrocytes. Cell Rep, 2017, 18(2): 468-481.
8. 陈竺, 孙关林, 陈赛娟, 等. 全反式维A酸诱导分化治疗急性早幼粒细胞白血病的机制研究. 上海第二医科大学学报, 2002, 22(5): S1-S4.
9. 朱新锋. 全反式维甲酸诱导分化肝癌干细胞作用研究. 昆明: 昆明医科大学, 2016.
10. Molinari F, Pin F, Gorini S A, et al. The mitochondrial metabolic reprogramming agent trimetazidine as an `exercise mimetic' in cachectic C26-bearing mice. J Cachexia Sarcopenia Muscle, 2017, 8(6): 954-973.
11. LaGory E L, Wu C, Taniguchi C M, et al. Suppression of PGC-1α is critical for reprogramming oxidative metabolism in renal cell carcinoma. Cell Rep, 2015, 12(1): 116-127.
12. Broecker-Preuss M, Becher-Boveleth N, Bockisch A, et al. Regulation of glucose uptake in lymphoma cell lines by c-MYC and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability. J Transl Med, 2017, 15(1): 158.
13. Eun K, Ham S W, Kim H. Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. BMB Rep, 2017, 50(3): 117-125.
14. Peng F, Wang J H, Fan W J, et al. Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. Oncogene, 2018, 37(8): 1062-1074.
15. Pouyafar A, Heydarabad M Z, Zade J A, et al. Modulation of lipolysis and glycolysis pathways in cancer stem cells changed multipotentiality and differentiation capacity toward endothelial lineage. Cell Biosci, 2019, 9: 30.
16. Cheng Y, Lu Y, Zhang D, et al. Metastatic cancer cells compensate for low energy supplies in hostile microenvironments with bioenergetic adaptation and metabolic reprogramming. Int J Oncol, 2018, 53(6): 2590-2604.
17. Zhou Kai, Yao Yueliang, He Zhicheng, et al. VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells. Cell Death Dis, 2018, 9(10): 988.
18. Gao Cuicui, Shen Yao, Jin Fang, et al. Cancer stem cells in small cell lung cancer cell line H446: higher dependency on oxidative phosphorylation and mitochondrial substrate-level phosphorylation than non-stem cancer cells. PLoS One, 2016, 11(5): e0154576.
19. Farge T, Saland E, de Toni F, et al. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. Cancer Discov, 2017, 7(7): 716-735.
20. De Luca A, Fiorillo M, Peiris-Pagès M, et al. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells. Oncotarget, 2015, 6(17): 14777-14795.
21. 李敏, 王红, 张斯亮, 等. 二甲双胍对甲状腺未分化癌细胞增殖和能量代谢的影响. 现代肿瘤医学, 2016, 24(11): 1694-1698.
22. Sancho P, Burgos-Ramos E, Tavera A, et al. MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab, 2015, 22(4): 590-605.
23. Zhang Haifeng, Wu Chengsheng, Alshareef A, et al. The PI3K/AKT/c-MYC axis promotes the acquisition of cancer stem-like features in esophageal squamous cell carcinoma. Stem Cells, 2016, 34(8): 2040-2051.
24. Izumi D, Ishimoto T, Miyake K, et al. Colorectal cancer stem cells acquire chemoresistance through the upregulation of F-box/WD repeat-containing protein 7 and the consequent degradation of c-Myc. Stem Cells, 2017, 35(9): 2027-2036.
25. 孙警辉. 力、化学刺激对肝癌干细胞迁移, 分化行为的影响及其相关分子机理. 重庆: 重庆大学, 2016.
26. Deng Dong, Xu Chao, Sun Pengcheng, et al. Crystal structure of the human glucose transporter GLUT1. Nature, 2014, 510(7503): 121-125.
27. Guo Zhengyang, Jia Junqiao, Yao Mingjie, et al. Diacylglycerol kinase gamma predicts prognosis and functions as a tumor suppressor by negatively regulating glucose transporter 1 in hepatocellular carcinoma. Exp Cell Res, 2018, 373(1-2): 211-220.
28. Wang Yaodong, Li Shengjiao, Liao Jianxing. Inhibition of glucose transporter 1(GLUT1) chemosensitized head and neck cancer cells to cisplatin. Technol Cancer Res Treat, 2013, 12(6): 525-535.
29. Kurahara H, Maemura K, Mataki Y, et al. Significance of glucose transporter type 1(GLUT-1) expression in the therapeutic strategy for pancreatic ductal adenocarcinoma. Ann Surg Oncol, 2018, 25(5): 1432-1439.
30. Yakisich J S, Azad N, Kaushik V, et al. The biguanides metformin and buformin in combination with 2-deoxy-glucose or WZB-117 inhibit the viability of highly resistant human lung cancer cells. Stem Cells Int, 2019: 6254269.
31. Libby C J, ZHANG Sixue, Benavides G A, et al. Identification of compounds that decrease glioblastoma growth and glucose uptake in vitro. ACS Chem Biol, 2018, 13(8): 2048-2057.
32. de Castro T B, Mota A L, Bordin-Junior N A, et al. Immunohistochemical expression of melatonin receptor MT1 and glucose transporter GLUT1 in human breast cancer. Anticancer Agents Med Chem, 2018, 18(15): 2110-2116.
33. Wang Yu, Yun Yuyu, Wu Bo, et al. FOXM1 promotes reprogramming of glucose metabolism in epithelial ovarian cancer cells via activation of GLUT1 and HK2 transcription. Oncotarget, 2016, 7(30): 47985-47997.
34. Wu Xueliang, Wang Likun, Yang Dongdong, et al. Effects of glut1 gene silencing on proliferation, differentiation, and apoptosis of colorectal cancer cells by targeting the TGF-β/PI3K-AKT-mTOR signaling pathway. J Cell Biochem, 2018, 119(2): 2356-2367.
35. Halestrap A P, Price N T. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochemical Journal, 1999, 343(2): 281-299.
36. Benjamin D, Robay D, Hindupur S K, et al. Dual inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD⁺ depletion in cancer cells. Cell Rep, 2018, 25(11): 3047-3058.
37. Miranda-Goncalves V, Granja S, Martinho O, et al. Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas. Oncotarget, 2016, 7(29): 46335-46353.
38. Romero-Cordoba S L, Rodriguez-Cuevas S A, Bautista-Pina V, et al. Loss of function of miR-342-3p results in MCT1 over-expression and contributes to oncogenic metabolic reprogramming in triple negative breast cancer. Sci Rep, 2018, 8(1): 12252.
39. Takada T, Takata K, Ashihara E. Inhibition of monocarboxylate transporter 1 suppresses the proliferation of glioblastoma stem cells. Journal of Physiological Sciences, 2016, 66(5): 387-396.
40. Kong S C, Nohr-Nielsen A, Zeeberg K A, et al. Monocarboxylate transporters MCT1 and MCT4 regulate migration and invasion of pancreatic ductal adenocarcinoma cells. Pancreas, 2016, 45(7): 1036-1047.
41. Van Hée V F, Labar D, Dehon G, et al. Radiosynthesis and validation of (±)-[¹⁸F]-3-fluoro-2-hydroxypropionate ([¹⁸F]-FLac) as a PET tracer of lactate to monitor MCT1-dependent lactate uptake in tumors. Oncotarget, 2017, 8(15): 24415-24428.

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Regulation of tumor cell glycometabolism and tumor therapy

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