Please wait a minute...
浙江大学学报（医学版）
J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (1): 32-40    DOI: 10.3724/zdxbyxb-2021-0040
    
Effect of glutamine metabolism on chemoresistance and its mechanism in tumors
HU Xinyang(),JIN Hongchuan,ZHU Liyuan()
Zhejiang Provincial Key Laboratory of Biotherapy，Sir Run Run Shaw Hospital，Zhejiang University School of Medicine，Hangzhou 310016，China
Download: HTML( 19 )   PDF(2996KB)
Export: BibTeX | EndNote (RIS)      

Abstract  

The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required substances for glycolysis and oxidative phosphorylation and affects the homeostasis of carbohydrate，fat and protein metabolism to induce the chemoresistance of tumor cells. Combination of chemotherapeutic agents with inhibitors specific to different components of glutamine metabolic pathway has obtained favorable clinical results on various tumors. Glutamine metabolic pathway plays a role in drug resistance of tumor cells in various ways. Firstly，the dynamic change of glutamine transporters can directly affect intracellular glutamine content thereby causing drug resistance; secondly，tumor stromal cells including adipocyte，fibroblast and metabolite from tumor microenvironment would give rise to immune-mediated drug resistance; thirdly，the expression and activity of key enzymes in glutamine metabolism also has a critical role in drug resistance of tumors. This article reviews the effects of glutamine metabolic pathway in the development of tumor chemoresistance，in terms of transporters，tumor microenvironment and metabolic enzymes，to provide insight for improving the therapeutic efficacy for drug-resistant tumors.

Key words： Glutamine      Cell metabolism      Tumor      Drug resistance      Review     
Received: 25 November 2020      Published: 15 May 2021
CLC:  R730.23  
  R730.23  
  A  
Corresponding Authors: ZHU Liyuan     E-mail: 21918520@zju.edu.cn;zly_smile@126.com
Service
E-mail this article
Add to my bookshelf
Add to citation manager
E-mail Alert
RSS
Articles by authors
HU Xinyang
JIN Hongchuan
ZHU Liyuan
Cite this article:

HU Xinyang,JIN Hongchuan,ZHU Liyuan. Effect of glutamine metabolism on chemoresistance and its mechanism in tumors. J Zhejiang Univ (Med Sci), 2021, 50(1): 32-40.

URL:

http://www.zjujournals.com/med/10.3724/zdxbyxb-2021-0040     OR     http://www.zjujournals.com/med/Y2021/V50/I1/32


谷氨酰胺代谢途径在肿瘤化疗耐药中的功能机制

肿瘤细胞代谢重编程表现为对谷氨酰胺等营养物质摄取增加，而谷氨酰胺代谢可为在肿瘤细胞中过度激活的糖酵解和氧化磷酸化反应提供所需的原料，还可通过影响糖、脂质、蛋白质代谢的稳态平衡直接诱发肿瘤细胞对化疗药物的抵抗。针对谷氨酰胺代谢途径不同环节的抑制剂联合常规化疗药物在多种耐药肿瘤中取得了较好的临床治疗效果。谷氨酰胺代谢途径主要通过以下几种方式在肿瘤细胞耐药中发挥作用：谷氨酰胺转运体活性动态变化直接影响细胞内谷氨酰胺含量而影响细胞耐药性；肿瘤微环境中脂肪细胞、成纤维细胞及微环境代谢物通过免疫应答等方式介导耐药发生；谷氨酰胺代谢途径关键酶的表达及活性改变对肿瘤细胞耐药性的产生也至关重要。本文从转运体、肿瘤微环境及代谢酶等层面总结了谷氨酰胺代谢途径在肿瘤细胞产生化疗药物抵抗过程中的调控功能及其作用方式，以期为今后提高耐药性肿瘤的临床治疗效果提供新的思路。


关键词： 谷氨酰胺,  细胞代谢,  肿瘤,  耐药性,  综述 
Figure 1 The illustration of glutamine metabolic pathway

谷氨酰胺代谢相关靶点

促进肿瘤耐药机制

耐药癌种

耐受药物

参考文献序号

转运体

?

溶质载体家族1成员5

促进谷氨酰胺进入线粒体，促进谷胱甘肽合成

胰腺癌

吉西他滨

28

通过AMPK-AKT信号通路抑制氧化磷酸化途径

结肠癌

二甲双胍

30

溶质载体家族1成员5抑制剂联合CB-839减少耐药细胞内谷胱甘肽产生，促进活性氧积累

肝癌

CB-839

45

溶质载体家族7成员8

激活mTOR通路，促进溶质载体家族7成员8的稳定，形成正反馈，促进耐药细胞摄取更多谷氨酰胺

胰腺癌

吉西他滨

29

溶质载体家族25成员22

促进三羧酸循环中谷氨酰胺代谢物琥珀酸的积累，促进DNA甲基化以及Wnt 信号通路激活

结肠癌

5-氟尿嘧啶

48

肿瘤微环境

?

肿瘤间质脂肪细胞

分泌大量谷氨酰胺，帮助白血病细胞抵抗左旋天冬酰胺酶的作用

急性淋巴细胞白血病

左旋天冬酰胺酶

34

肿瘤间质成纤维细胞

微囊蛋白1表达下降，自噬水平升高，促进谷氨酰胺向肿瘤实质细胞转移

乳腺癌

他莫昔芬

37

谷氨酰胺代谢酶

?

谷氨酰胺酶

表达增加，细胞对谷氨酰胺代谢依赖度增加，α酮戊二酸水平增高

黑色素瘤

BRAF抑制剂

39

多形性胶质母细胞瘤

雷帕霉素、PP242

40

谷氨酸脱氢酶、谷氨酰胺酶

ADI-PEG20诱导耐药细胞短期内C-MYC表达，进而促进谷氨酸脱氢酶和谷氨酰胺酶表达，提高谷氨酰胺代谢通路的活性

黑色素瘤

ADI-PEG20

41

谷氨酸脱氢酶

低氧情况下缺氧诱导因子1α蛋白水平升高，促进谷氨酸脱氢酶表达，使得肿瘤细胞对谷氨酰胺的摄取和利用增加

肺癌

顺铂

42

调控氧化磷酸化

 ?

PPARδ

促进耐药细胞对谷氨酰胺依赖，并调节氧化还原稳态，促进耐药细胞增殖

肝癌

索拉菲尼

43

其他途径

 ?

MYC

表达上调，调节谷氨酰胺诱导的未折叠蛋白反应，使得肿瘤细胞对低糖环境的耐受增加

乳腺癌

他莫昔芬、氟维司群

46

谷氨酰胺代谢通路多靶点

耐药细胞依赖谷氨酰胺代谢提供的氮源来维持蛋白质的异常糖基化，同时维持还原性稳态

胰腺癌

吉西他滨

47

α酮戊二酸

肿瘤细胞DNA损伤修复酶ALKBH的活性发挥依赖于细胞内α酮戊二酸水平

黑色素瘤、结肠癌

甲磺酸甲酯

49
Table 1 Summary of glutamine metabolism-related antineoplastic drug resistance
[1]   SONG H, LIU D, DONG S, et al. Epitranscriptomics and epiproteomics in cancer drug resistance:therapeutic implications[J]. Sig Transduct Target Ther, 2020, 5(1): 193.
doi: 10.1038/s41392-020-00300-w
[2]   VASAN N, BASELGA J, HYMAN D M . A view on drug resistance in cancer[J]. Nature, 2019, 575(7782): 299-309.
doi: 10.1038/s41586-019-1730-1
[3]   FENDT S M, FREZZA C, EREZ A . Targeting metabolic plasticity and flexibility dynamics for cancer therapy[J]. Cancer Discov, 2020, 10(12): 1797-1807.
doi: 10.1158/2159-8290.CD-20-0844
[4]   ZHAO Y, BUTLER E B, TAN M . Targeting cellular metabolism to improve cancer therapeutics[J/OL]. Cell Death Dis, 2013, 4(3): e532.
doi: 10.1038/cddis.2013.60
[5]   KOPPENOL W H, BOUNDS P L, DANG C V . Otto Warburg’s contributions to current concepts of cancer metabolism[J]. Nat Rev Cancer, 2011, 11(5): 325-337.
doi: 10.1038/nrc3038
[6]   LIBERTI M V, LOCASALE J W . The Warburg effect:How does it benefit cancer cells?[J]. Trends Biochem Sci, 2016, 41(3): 211-218.
doi: 10.1016/j.tibs.2015.12.001
[7]   VANDER HEIDEN M G . Targeting cancer metabolism:a therapeutic window opens[J]. Nat Rev Drug Discov, 2011, 10(9): 671-684.
doi: 10.1038/nrd3504
[8]   SON J, LYSSIOTIS C A, YING H, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway[J]. Nature, 2013, 496(7443): 101-105.
doi: 10.1038/nature12040
[9]   EREZ A, KOLODKIN-GAL I . From prokaryotes to cancer:Glutamine flux in multicellular units[J]. Trends Endocrinol Metab, 2017, 28(9): 637-644.
doi: 10.1016/j.tem.2017.05.007
[10]   SEMENZA G L . HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations[J]. J Clin Invest, 2013, 123(9): 3664-3671.
doi: 10.1172/JCI67230
[11]   SCALISE M, POCHINI L, GALLUCCIO M, et al. Glutamine transport. From energy supply to sensing and beyond[J]. BioChim Biophysica Acta （BBA） - Bioenergetics, 2016, 1857(8): 1147-1157.
doi: 10.1016/j.bbabio.2016.03.006
[12]   WISE D R, WARD P S, SHAY J E S, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability[J]. Proc Natl Acad Sci USA, 2011, 108(49): 19611-19616.
doi: 10.1073/pnas.1117773108
[13]   METALLO C M, GAMEIRO P A, BELL E L, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia[J]. Nature, 2012, 481(7381): 380-384.
doi: 10.1038/nature10602
[14]   LACEY J M, WILMORE D W . Is glutamine a conditionally essential amino acid?[J]. Nutrition Rev, 2009, 48(8): 297-309.
doi: 10.1111/j.1753-4887.1990.tb02967.x
[15]   RUBIN A L. Suppression of transformation by and growth adaptation to low concentrations of glutamine in NIH-3T3 cells[J]. Cancer Res，1990，50（9）:2832–2839 .
[16]   SCALISE M, POCHINI L, GALLUCCIO M, et al. Glutamine transport and mitochondrial metabolism in cancer cell growth[J]. Front Oncol, 2017, 306.
doi: 10.3389/fonc.2017.00306
[17]   FERREIRA L M R, HEBRANT A, DUMONT J E . Metabolic reprogramming of the tumor[J]. Oncogene, 2012, 31(36): 3999-4011.
doi: 10.1038/onc.2011.576
[18]   HUANG Q, TAN Y, YIN P, et al. Metabolic characte- rization of hepatocellular carcinoma using nontargeted tissue metabolomics[J]. Cancer Res, 2013, 73(16): 4992-5002.
doi: 10.1158/0008-5472.CAN-13-0308
[19]   VANDER HEIDEN M G, CANTLEY L C, THOMPSON C B . Understanding the warburg effect:The metabolic requirements of cell proliferation[J]. Science, 2009, 324(5930): 1029-1033.
doi: 10.1126/science.1160809
[20]   PASTORE A, PIEMONTE F . S-glutathionylation signaling in cell biology:Progress and prospects[J]. Eur J Pharmaceutical Sci, 2012, 46(5): 279-292.
doi: 10.1016/j.ejps.2012.03.010
[21]   MOHAMED A, DENG X, KHURI F R, et al. Altered glutamine metabolism and therapeutic opportunities for lung cancer[J]. Clin Lung Cancer, 2014, 15(1): 7-15.
doi: 10.1016/j.cllc.2013.09.001
[22]   SOUBA W W, STREBEL F R, BULL J M, et al. Interorgan glutamine metabolism in the tumor-bearing rat[J]. J Surgical Res, 1988, 44(6): 720-726.
doi: 10.1016/0022-4804（88）90106-0
[23]   DUDRICK P S, INOUE Y, ESPAT N J, et al. Na +- dependent glutamine transport in the liver of tumour-bearing rats[J] . Surg Oncol, 1993, 2(3): 205-215.
doi: 10.1016/0960-7404（93）90008-m
[24]   CHEN M K, ESPAT N J, BLAND K I, et al. Influence of progressive tumor growth on glutamine metabolism in skeletal muscle and kidney[J]. Ann Surgery, 1993, 217(6): 655-667.
doi: 10.1097/00000658-199306000-00007
[25]   HENSLEY C T, WASTI A T, DEBERARDINIS R J . Glutamine and cancer:cell biology，physiology，and clinical opportunities[J]. J Clin Invest, 2013, 123(9): 3678-3684.
doi: 10.1172/JCI69600
[26]   DURáN R V, OPPLIGER W, ROBITAILLE A M, et al. Glutaminolysis activates Rag-mTORC1 signaling[J]. Mol Cell, 2012, 47(3): 349-358.
doi: 10.1016/j.molcel.2012.05.043
[27]   GANAPATHY V, THANGARAJU M, PRASAD P D . Nutrient transporters in cancer:relevance to Warburg hypothesis and beyond[J]. Pharmacol Ther, 2009, 121(1): 29-40.
doi: 10.1016/j.pharmthera.2008.09.005
[28]   YOO H C, PARK S J, NAM M, et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells[J]. Cell Metab, 2020, 31(2): 267-283.e12.
doi: 10.1016/j.cmet.2019.11.020
[29]   FENG M, XIONG G, CAO Z, et al. LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer[J]. J Exp Clin Cancer Res, 2018, 37(1): 274.
doi: 10.1186/s13046-018-0947-4
[30]   KIM J H, LEE K J, SEO Y, et al. Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism[J]. Sci Rep, 2018, 8(1): 409.
doi: 10.1038/s41598-017-18762-4
[31]   BLüHER M . Obesity:global epidemiology and patho- genesis[J]. Nat Rev Endocrinol, 2019, 15(5): 288-298.
doi: 10.1038/s41574-019-0176-8
[32]   BOCHET L, LEHUéDé C, DAUVILLIER S, et al. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer[J]. Cancer Res, 2013, 73(18): 5657-5668.
doi: 10.1158/0008-5472.CAN-13-0530
[33]   CALLE E E, KAAKS R . Overweight，obesity and cancer:epidemiological evidence and proposed mechanisms[J]. Nat Rev Cancer, 2004, 4(8): 579-591.
doi: 10.1038/nrc1408
[34]   EHSANIPOUR E A, SHENG X, BEHAN J W, et al. Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine[J]. Cancer Res, 2013, 73(10): 2998-3006.
doi: 10.1158/0008-5472.CAN-12-4402
[35]   PETROVA V, ANNICCHIARICO-PETRUZZELLI M, MELINO G, et al. The hypoxic tumour microenvironment[J]. Oncogenesis, 2018, 7(1): 10.
doi: 10.1038/s41389-017-0011-9
[36]   MARTINEZ-OUTSCHOORN U E, LISANTI M P, SOTGIA F . Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells，fueling tumor growth[J]. Seminars Cancer Biol, 2014, 47-60.
doi: 10.1016/j.semcancer.2014.01.005
[37]   KO Y H, LIN Z, FLOMENBERG N, et al. Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells[J]. Cancer Biol Ther, 2011, 12(12): 1085-1097.
doi: 10.4161/cbt.12.12.18671
[38]   MUIR A, DANAI L V, GUI D Y, et al. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition[J/OL]. eLife, 2017, e27713.
doi: 10.7554/eLife.27713
[39]   BAENKE F, CHANETON B, SMITH M, et al. Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells[J]. Mol Oncol, 2016, 10(1): 73-84.
doi: 10.1016/j.molonc.2015.08.003
[40]   TANAKA K, SASAYAMA T, IRINO Y, et al. Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment[J]. J Clin Invest, 2015, 125(4): 1591-1602.
doi: 10.1172/JCI78239
[41]   LONG Y, TSAI W B, WANGPAICHITR M, et al. Arginine deiminase resistance in melanoma cells is associated with metabolic reprogramming，glucose dependence，and glutamine addiction[J]. Mol Cancer Ther, 2013, 12(11): 2581-2590.
doi: 10.1158/1535-7163.MCT-13-0302
[42]   JIANG Z F, WANG M, XU J L, et al. Hypoxia promotes mitochondrial glutamine metabolism through HIF1α-GDH pathway in human lung cancer cells[J]. Biochem BioPhys Res Commun, 2017, 483(1): 32-38.
doi: 10.1016/j.bbrc.2017.01.015
[43]   KIM M J, CHOI Y K, PARK S Y, et al. PPARδ reprograms glutamine metabolism in sorafenib-resistant HCC[J]. Mol Cancer Res, 2017, 15(9): 1230-1242.
doi: 10.1158/1541-7786.MCR-17-0061
[44]   LIAO J, LIU P P, HOU G, et al. Regulation of stem-like cancer cells by glutamine through β-catenin pathway mediated by redox signaling[J]. Mol Cancer, 2017, 16(1): 51.
doi: 10.1186/s12943-017-0623-x
[45]   JIN H, WANG S, ZAAL E A, et al. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer[J/OL]. eLife, 2020, e56749.
doi: 10.7554/eLife.56749
[46]   SHAJAHAN-HAQ A N, COOK K L, SCHWARTZ-ROBERTS J L, et al. MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer[J]. Mol Cancer, 2014, 13(1): 239.
doi: 10.1186/1476-4598-13-239
[47]   CHEN R, LAI L A, SULLIVAN Y, et al. Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer[J]. Sci Rep, 2017, 7(1): 7950.
doi: 10.1038/s41598-017-08436-6
[48]   WONG C C, XU J, BIAN X, et al. In colorectal cancer cells with mutant KRAS，SLC25A22-mediated glutaminolysis reduces DNA demethylation to increase WNT Signaling，stemness，and drug resistance[J]. Gastroenterology, 2020, 159(6): 2163-2180.e6.
doi: 10.1053/j.gastro.2020.08.016
[1] SHAO Yiming,SU Lide,HAO Rui,WANG Qianqian,NARANMANDURA Hua. Advances on molecular mechanism of hepatitis B virus-induced hepatocellular carcinoma[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 113-122.
[2] HAN Hengyi,FENG Fan,LI Haitao. Research advances on epigenetics and cancer metabolism[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 1-16.
[3] CHEN Fei,YU Min,ZHONG Yonghong,HUA Wen,HUANG Huaqiong. The role of neutrophils in asthma[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 123-130.
[4] YAN Jing,ZHANG Tingting,ZHAO Kui. Application of molecular probes in nuclear imaging of neuroendocrine tumors[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 131-137.
[5] ZHANG Mingquan,PAN Junchen,HUANG Peng. Interaction between RAS gene and lipid metabolism in cancer[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 17-22.
[6] MENG Ying,WANG Qifei,LYU Zhimin. Cholesterol metabolism and tumor[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 23-31.
[7] YANG Zeran,ZHANG Xin,MA Jie,JIN Li,HE Xujun. Expression of tumor-associated vascular insulin receptor in colorectal cancer and its relationship with tumor pathological features[J]. J Zhejiang Univ (Med Sci), 2020, 49(6): 725-731.
[8] ZHU Huiqi,YING Kejing. Tissue factors and venous thromboembolism in cancer patients[J]. J Zhejiang Univ (Med Sci), 2020, 49(6): 772-778.
[9] LIN Cuicui,CHEN Zhengyun,WANG Chunyan,XI Yongmei. Research progress on biomarkers for endometriosis based on lipidomics[J]. J Zhejiang Univ (Med Sci), 2020, 49(6): 779-784.
[10] LI Mengyao,LIU Pan,KE Yuehai,ZHANG Xue. Research progress on macrophage in radiation induced lung injury[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 623-628.
[11] HAN Xue,JIANG Guojun,SHI Qiaojuan. Effects of antihyperglycemics on endothelial progenitor cells[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 629-636.
[12] DUAN Runping,XU Yesheng,ZHENG Libin,YAO Yufeng. Research progress on etiologic diagnosis of ocular viral diseases[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 644-650.
[13] WU Wei,XU Jian. Research progress on the role of pentraxin 3 in polycystic ovary syndrome[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 637-643.
[14] XU Qinglin,LOU Guodong,WANG Tiantian,ZHANG Lisan. Advances in treatment of narcolepsy[J]. J Zhejiang Univ (Med Sci), 2020, 49(4): 419-424.
[15] JIANG Peiran,WANG Zhiping. Progress on axon regeneration in model organisms[J]. J Zhejiang Univ (Med Sci), 2020, 49(4): 500-507.