中国癌症杂志 ›› 2024, Vol. 34 ›› Issue (1): 97-103.doi: 10.19401/j.cnki.1007-3639.2024.01.007
刘雪柔1,2(), 杨玉梅1,2, 赵倩1,2, 荣翔宇1,2, 刘伟1,2, 郑瑞洁1,2, 庞金龙1,2, 李娴1,2, 李姗姗1,2(
)
收稿日期:
2023-10-26
修回日期:
2023-12-20
出版日期:
2024-01-30
发布日期:
2024-02-05
通信作者:
李姗姗(ORCID: 0000-0003-2201-6321),博士,副教授、硕士研究生导师。
作者简介:
刘雪柔(ORCID: 0009-0004-2260-8153),硕士。
基金资助:
LIU Xuerou1,2(), YANG Yumei1,2, ZHAO Qian1,2, RONG Xiangyu1,2, LIU Wei1,2, ZHENG Ruijie1,2, PANG Jinlong1,2, LI Xian1,2, LI Shanshan1,2(
)
Received:
2023-10-26
Revised:
2023-12-20
Published:
2024-01-30
Online:
2024-02-05
Contact:
LI Shanshan.
文章分享
摘要:
肿瘤转移是导致癌症患者高死亡率的主要原因。谷氨酰胺在肿瘤的恶性进展中发挥重要作用,近年来研究发现,谷氨酰胺与肿瘤转移密切相关,谷氨酰胺作为肿瘤细胞重要的碳源和氮源,不仅影响肿瘤细胞的增殖,还参与调控肿瘤细胞的迁移和侵袭。此外,谷氨酰胺代谢过程中的各种酶及转运体通过不同的信号转导通路参与肿瘤转移过程。本文综述近年来谷氨酰胺在肿瘤转移中作用的研究进展,并梳理有关治疗靶点,以期为临床治疗肿瘤转移提供新的策略。
中图分类号:
刘雪柔, 杨玉梅, 赵倩, 荣翔宇, 刘伟, 郑瑞洁, 庞金龙, 李娴, 李姗姗. 谷氨酰胺代谢相关蛋白在肿瘤转移中的作用研究进展[J]. 中国癌症杂志, 2024, 34(1): 97-103.
LIU Xuerou, YANG Yumei, ZHAO Qian, RONG Xiangyu, LIU Wei, ZHENG Ruijie, PANG Jinlong, LI Xian, LI Shanshan. Research progress on the role of glutamine metabolism-related proteins in tumor metastasis[J]. China Oncology, 2024, 34(1): 97-103.
[1] |
REN L, RUIZ-RODADO V, DOWDY T, et al. Glutaminase-1 (GLS1) inhibition limits metastatic progression in osteosarcoma[J]. Cancer Metab, 2020, 8: 4.
doi: 10.1186/s40170-020-0209-8 pmid: 32158544 |
[2] | FARES J, FARES M Y, KHACHFE H H, et al. Molecular principles of metastasis: a hallmark of cancer revisited[J]. Signal Transduct Target Ther, 2020, 5(1): 28. |
[3] |
BERGERS G, FENDT S M. The metabolism of cancer cells during metastasis[J]. Nat Rev Cancer, 2021, 21(3): 162-180.
doi: 10.1038/s41568-020-00320-2 pmid: 33462499 |
[4] |
LEONE R D, ZHAO L, ENGLERT J M, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion[J]. Science, 2019, 366(6468): 1013-1021.
doi: 10.1126/science.aav2588 pmid: 31699883 |
[5] |
WANG Y Y, BAI C S, RUAN Y X, et al. Coordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia[J]. Nat Commun, 2019, 10(1): 201.
doi: 10.1038/s41467-018-08033-9 pmid: 30643150 |
[6] |
KODAMA M, OSHIKAWA K, SHIMIZU H, et al. A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer[J]. Nat Commun, 2020, 11(1): 1320.
doi: 10.1038/s41467-020-15136-9 pmid: 32184390 |
[7] |
ADHIKARY G, SHRESTHA S, NASELSKY W, et al. Mesothelioma cancer cells are glutamine addicted and glutamine restriction reduces YAP1 signaling to attenuate tumor formation[J]. Mol Carcinog, 2023, 62(4): 438-449.
doi: 10.1002/mc.v62.4 |
[8] |
JIANG B, ZHANG J, ZHAO G H, et al. Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis[J]. Mol Cell, 2022, 82(10): 1821-1835.e6.
doi: 10.1016/j.molcel.2022.03.016 pmid: 35381197 |
[9] |
VILLAR V H, ALLEGA M F, DESHMUKH R, et al. Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer[J]. Nat Chem Biol, 2023, 19(3): 292-300.
doi: 10.1038/s41589-022-01154-9 |
[10] |
SHANG M, CAPPELLESSO F, AMORIM R, et al. Macrophage-derived glutamine boosts satellite cells and muscle regeneration[J]. Nature, 2020, 587(7835): 626-631.
doi: 10.1038/s41586-020-2857-9 |
[11] |
DORAI T, PINTO J T, DENTON T T, et al. The metabolic importance of the glutaminase Ⅱ pathway in normal and cancerous cells[J]. Anal Biochem, 2022, 644: 114083.
doi: 10.1016/j.ab.2020.114083 |
[12] |
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: S1550-4131(19)30664-3 pmid: 31866442 |
[13] |
GUO C S, YOU Z Y, SHI H, et al. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity[J]. Nature, 2023, 620(7972): 200-208.
doi: 10.1038/s41586-023-06299-8 |
[14] | LIU R, HONG R X, WANG Y, et al. Defect of SLC38A3 promotes epithelial-mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma[J]. Chung Kuo Yen Cheng Yen Chiu, 2020, 32(5): 547-563. |
[15] |
CHEN Y Y, TAN L, GAO J, et al. Targeting glutaminase 1 (GLS1) by small molecules for anticancer therapeutics[J]. Eur J Med Chem, 2023, 252: 115306.
doi: 10.1016/j.ejmech.2023.115306 |
[16] |
HAN T Y, WANG P C, WANG Y N, et al. FAIM regulates autophagy through glutaminolysis in lung adenocarcinoma[J]. Autophagy, 2022, 18(6): 1416-1432.
doi: 10.1080/15548627.2021.1987672 |
[17] |
YU Y, YU X H, FAN C L, et al. Targeting glutaminase-mediated glutamine dependence in papillary thyroid cancer[J]. J Mol Med, 2018, 96(8): 777-790.
doi: 10.1007/s00109-018-1659-0 |
[18] |
LIU H Y, ZHANG H S, LIU M Y, et al. GLS1 depletion inhibited colorectal cancer proliferation and migration via redox/Nrf2/autophagy-dependent pathway[J]. Arch Biochem Biophys, 2021, 708: 108964.
doi: 10.1016/j.abb.2021.108964 |
[19] |
CAI J, CHEN Z Q, WANG J G, et al. circHECTD1 facilitates glutaminolysis to promote gastric cancer progression by targeting miR-1256 and activating β-catenin/c-Myc signaling[J]. Cell Death Dis, 2019, 10(8): 576.
doi: 10.1038/s41419-019-1814-8 pmid: 31371702 |
[20] |
PASTUSHENKO I, BLANPAIN C. EMT transition states during tumor progression and metastasis[J]. Trends Cell Biol, 2019, 29(3): 212-226.
doi: S0962-8924(18)30201-0 pmid: 30594349 |
[21] |
LI B H, CAO Y J, MENG G, et al. Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway[J]. EBioMedicine, 2019, 39: 239-254.
doi: S2352-3964(18)30567-X pmid: 30555042 |
[22] |
LUKEY M J, CLUNTUN A A, KATT W P, et al. Liver-type glutaminase GLS2 is a druggable metabolic node in luminal-subtype breast cancer[J]. Cell Rep, 2019, 29(1): 76-88.e7.
doi: S2211-1247(19)31131-3 pmid: 31577957 |
[23] | SUZUKI S, VENKATESH D, KANDA H, et al. GLS2 is a tumor suppressor and a regulator of ferroptosis in hepatocellular carcinoma[J]. Cancer Res, 2022, 82(18): 3209-3222. |
[24] |
ZHANG C, LIU J, ZHAO Y H, et al. Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis[J]. Elife, 2016, 5: e10727.
doi: 10.7554/eLife.10727 |
[25] |
KUO T C, CHEN C K, HUA K T, et al. Glutaminase 2 stabilizes dicer to repress snail and metastasis in hepatocellular carcinoma cells[J]. Cancer Lett, 2016, 383(2): 282-294.
doi: 10.1016/j.canlet.2016.10.012 |
[26] |
DIAS M M, ADAMOSKI D, DOS REIS L M, et al. GLS2 is protumorigenic in breast cancers[J]. Oncogene, 2020, 39(3): 690-702.
doi: 10.1038/s41388-019-1007-z pmid: 31541193 |
[27] |
BRABLETZ S, SCHUHWERK H, BRABLETZ T, et al. Dynamic EMT: a multi-tool for tumor progression[J]. EMBO J, 2021, 40(18): e108647.
doi: 10.15252/embj.2021108647 |
[28] |
NALLASAMY P, NIMMAKAYALA R K, KARMAKAR S, et al. Pancreatic tumor microenvironment factor promotes cancer stemness via SPP1-CD44 axis[J]. Gastroenterology, 2021, 161(6): 1998-2013.e7.
doi: 10.1053/j.gastro.2021.08.023 pmid: 34418441 |
[29] |
XIE W, JIANG Q W, WU X J, et al. IKBKE phosphorylates and stabilizes Snail to promote breast cancer invasion and metastasis[J]. Cell Death Differ, 2022, 29(8): 1528-1540.
doi: 10.1038/s41418-022-00940-1 pmid: 35066576 |
[30] |
LEE M Y, LIM S, KIM Y S, et al. DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition[J]. J Allergy Clin Immunol, 2022, 149(1): 340-357.
doi: 10.1016/j.jaci.2021.04.024 |
[31] |
LIANG Y P, CEN J J, HUANG Y, et al. CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug[J]. Mol Cancer, 2022, 21(1): 224.
doi: 10.1186/s12943-022-01694-7 pmid: 36536414 |
[32] |
ANG H L, MOHAN C D, SHANMUGAM M K, et al. Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds[J]. Med Res Rev, 2023, 43(4): 1141-1200.
doi: 10.1002/med.v43.4 |
[33] |
RECOUVREUX M V, MOLDENHAUER M R, GALENKAMP K M O, et al. Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer[J]. J Exp Med, 2020, 217(9): e20200388.
doi: 10.1084/jem.20200388 |
[34] |
CHEN X T, HUANG L L, YANG T T, et al. METTL3 promotes esophageal squamous cell carcinoma metastasis through enhancing GLS2 expression[J]. Front Oncol, 2021, 11: 667451.
doi: 10.3389/fonc.2021.667451 |
[35] |
KIM G W, LEE D H, JEON Y H, et al. Glutamine synthetase as a therapeutic target for cancer treatment[J]. Int J Mol Sci, 2021, 22(4): 1701.
doi: 10.3390/ijms22041701 |
[36] |
ZHANG R, ZHU J C, HU H, et al. MicroRNA-140-5p suppresses invasion and proliferation of glioma cells by targeting glutamate-ammonia ligase (GLUL)[J]. Neoplasma, 2020, 67(2): 371-378.
doi: 10.4149/neo_2020_190514N432 pmid: 31986891 |
[37] |
MENGA A, FAVIA M, SPERA I, et al. N-acetylaspartate release by glutaminolytic ovarian cancer cells sustains protumoral macrophages[J]. EMBO Rep, 2021, 22(9): e51981.
doi: 10.15252/embr.202051981 |
[38] |
XUAN D T M, WU C C, WANG W J, et al. Glutamine synthetase regulates the immune microenvironment and cancer development through the inflammatory pathway[J]. Int J Med Sci, 2023, 20(1): 35-49.
doi: 10.7150/ijms.75625 pmid: 36619229 |
[39] |
QUAIL D F, JOYCE J A. Microenvironmental regulation of tumor progression and metastasis[J]. Nat Med, 2013, 19(11): 1423-1437.
doi: 10.1038/nm.3394 pmid: 24202395 |
[40] |
LIN Y X, XU J X, LAN H Y. Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applications[J]. J Hematol Oncol, 2019, 12(1): 76.
doi: 10.1186/s13045-019-0760-3 |
[41] |
WANG Y, GAO R F, LI J P, et al. Downregulation of hsa_circ_0074854 suppresses the migration and invasion in hepatocellular carcinoma via interacting with HuR and via suppressing exosomes-mediated macrophage M2 polarization[J]. Int J Nanomedicine, 2021, 16: 2803-2818.
doi: 10.2147/IJN.S284560 |
[42] |
WEI C, YANG C G, WANG S Y, et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis[J]. Mol Cancer, 2019, 18(1): 64.
doi: 10.1186/s12943-019-0976-4 pmid: 30927925 |
[43] |
PALMIERI E M, MENGA A, MARTÍN-PÉREZ R, et al. Pharmacologic or genetic targeting of glutamine synthetase skews macrophages toward an M1-like phenotype and inhibits tumor metastasis[J]. Cell Rep, 2017, 20(7): 1654-1666.
doi: S2211-1247(17)31033-1 pmid: 28813676 |
[44] |
MENGA A, SERRA M, TODISCO S, et al. Glufosinate constrains synchronous and metachronous metastasis by promoting anti-tumor macrophages[J]. EMBO Mol Med, 2020, 12(10): e11210.
doi: 10.15252/emmm.201911210 |
[45] |
WANG T, CAI B L, DING M C, et al. C-myc overexpression promotes oral cancer cell proliferation and migration by enhancing glutaminase and glutamine synthetase activity[J]. Am J Med Sci, 2019, 358(3): 235-242.
doi: S0002-9629(19)30219-8 pmid: 31324362 |
[46] |
BODINEAU C, TOMÉ M, MURDOCH P D S, et al. Glutamine, MTOR and autophagy: a multiconnection relationship[J]. Autophagy, 2022, 18(11): 2749-2750.
doi: 10.1080/15548627.2022.2062875 |
[47] |
JIN L T, CHUN J, PAN C Y, et al. The PLAG1-GDH1 axis promotes anoikis resistance and tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung cancer[J]. Mol Cell, 2018, 69(1): 87-99.e7.
doi: S1097-2765(17)30884-5 pmid: 29249655 |
[48] |
KANG J, CHUN J, HWANG J S, et al. EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR-activated lung cancer[J]. Cell Rep, 2022, 41(11): 111827.
doi: 10.1016/j.celrep.2022.111827 |
[49] |
LIU G J, ZHU J, YU M L, et al. Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients[J]. J Transl Med, 2015, 13: 144.
doi: 10.1186/s12967-015-0500-6 pmid: 25947346 |
[50] | MAO L, HONG X, XU L W, et al. Sirtuin 4 inhibits prostate cancer progression and metastasis by modulating p21 nuclear translocation and glutamate dehydrogenase 1 ADP-ribosylation[J]. J Oncol, 2022, 2022: 5498743. |
[51] |
LEE H T, HUANG C H, CHEN W C, et al. Transglutaminase 2 promotes migration and invasion of lung cancer cells[J]. Oncol Res, 2018, 26(8): 1175-1182.
doi: 10.3727/096504018X15149761920868 |
[52] |
ECKERT R L. Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target[J]. Mol Carcinog, 2019, 58(6): 837-853.
doi: 10.1002/mc.v58.6 |
[53] |
KANG S, OH S C, MIN B W, et al. Transglutaminase 2 regulates self-renewal and stem cell marker of human colorectal cancer stem cells[J]. Anticancer Res, 2018, 38(2): 787-794.
pmid: 29374703 |
[54] |
JIA C C, WANG G Y, WANG T T, et al. Cancer-associated fibroblasts induce epithelial-mesenchymal transition via the transglutaminase 2-dependent IL-6/IL6R/STAT3 axis in hepatocellular carcinoma[J]. Int J Biol Sci, 2020, 16(14): 2542-2558.
doi: 10.7150/ijbs.45446 |
[55] |
ASHOUR A A, GURBUZ N, ALPAY S N, et al. Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion[J]. J Cell Mol Med, 2014, 18(11): 2235-2251.
doi: 10.1111/jcmm.12361 pmid: 25215932 |
[56] |
WANG X F, YU Z J, ZHOU Q, et al. Tissue transglutaminase-2 promotes gastric cancer progression via the ERK1/2 pathway[J]. Oncotarget, 2016, 7(6): 7066-7079.
doi: 10.18632/oncotarget.6883 pmid: 26771235 |
[57] |
DING Y, LIU P F, ZHANG S S, et al. Screening pathogenic genes in oral squamous cell carcinoma based on the mRNA expression microarray data[J]. Int J Mol Med, 2018, 41(6): 3597-3603.
doi: 10.3892/ijmm.2018.3514 pmid: 29512771 |
[58] |
CSANADI A, OSER A, AUMANN K, et al. Overexpression of SLC1a5 in lymph node metastases outperforms assessment in the primary as a negative prognosticator in non-small cell lung cancer[J]. Pathology, 2018, 50(3): 269-275.
doi: 10.1016/j.pathol.2017.10.016 |
[59] |
DING M C, BU X, LI Z H, et al. NDRG2 ablation reprograms metastatic cancer cells towards glutamine dependence via the induction of ASCT2[J]. Int J Biol Sci, 2020, 16(16): 3100-3115.
doi: 10.7150/ijbs.48066 |
[60] |
WANG Y H, FU L, CUI M Q, et al. Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1[J]. Cancer Lett, 2017, 393: 8-15.
doi: S0304-3835(17)30078-2 pmid: 28202352 |
[61] |
ZHANG D J, ZHAO L, SHEN Q, et al. Down-regulation of KIAA1199/CEMIP by miR-216a suppresses tumor invasion and metastasis in colorectal cancer[J]. Int J Cancer, 2017, 140(10): 2298-2309.
doi: 10.1002/ijc.30656 pmid: 28213952 |
[62] |
MOROTTI M, ZOIS C E, EL-ANSARI R, et al. Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple-negative breast cancer[J]. Br J Cancer, 2021, 124(2): 494-505.
doi: 10.1038/s41416-020-01113-y |
[63] |
NAJUMUDEEN A K, CETECI F, FEY S K, et al. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer[J]. Nat Genet, 2021, 53(1): 16-26.
doi: 10.1038/s41588-020-00753-3 pmid: 33414552 |
[64] |
INNAO V, RIZZO V, ALLEGRA A G, et al. Promising anti-mitochondrial agents for overcoming acquired drug resistance in multiple myeloma[J]. Cells, 2021, 10(2): 439.
doi: 10.3390/cells10020439 |
[65] |
RICHARD S M, MARTINEZ MARIGNAC V L. Sensitization to oxaliplatin in HCT116 and HT29 cell lines by metformin and ribavirin and differences in response to mitochondrial glutaminase inhibition[J]. J Cancer Res Ther, 2015, 11(2): 336-340.
doi: 10.4103/0973-1482.157317 pmid: 26148596 |
[66] |
HALAMA A, KULINSKI M, DIB S S, et al. Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis[J]. Cancer Lett, 2018, 430: 133-147.
doi: S0304-3835(18)30342-2 pmid: 29777783 |
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