Objective To explore the role of glutamine fructose-6-phosphate transaminase 2 (GFPT2) in the migration of prostate cancer cells and its underlying molecular mechanism.
Methods The mRNA expression of GFPT2 in RWPE-1 and five human prostate cancer cell lines was detected by qRT-PCR. Analyzing the immunohistochemistry data of GFPT2 from the Human Protein Atlas (HPA) for normal prostate tissue and prostate cancer tissue. The GFPT2 knockdown cell models were established using siRNA. Cell migration ability was assessed through Transwell assay and Cell scratch assay. The biomarkers of epithelial-mesenchymal transition (EMT) were determined by Western blot.
Results Compared with RWPE-1 cells, GFPT2 mRNA expression was significantly upregulated in high-metastatic prostate cancer cell lines (PC3 and DU145). Immunohistochemistry data from the HPA indicated that the expression level of GFPT2 in prostate cancer tissue was significantly higher than in normal prostate tissue. In vitro, GFPT2 knockdown markedly reduced O-GlcNAcylation levels in prostate cancer cells. Additionally, GFPT2 knockdown significantly suppressed the migration of prostate cancer cells, upregulated the protein level of E-cadherins, and downregulated the protein levels of N-cadherin and Vimentin.
Conclusion GFPT2 is upregulated in prostate cancer and promotes tumor cell migration, making it a promising new target for inhibiting prostate cancer metastasis.
1.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
2.Feldman BJ, Feldman D. The development of androgen-independent prostate cancer[J]. Nat Rev Cancer, 2001, 1(1): 34-45. DOI: 10.1038/35094009.
3.邓通, 蔡林, 陈征, 等. 1990年与2017年中国前列腺癌疾病负担分析[J]. 医学新知, 2020, 30(4): 252-259. [Deng T, Cai L, Chen Z, et al. Analysis of the burden of prostate cancer in China in 1990 and 2017[J]. Yixue Xinzhi Zazhi, 2020, 30(4): 252-259.] DOI: 10.12173/j.issn.1004-5511.2020.04.01.
4.黄海, 程必盛, 黄健, 等. 2024年欧洲泌尿外科学会年会: 前列腺癌研究的前沿探索与未来趋势[J]. 中华腔镜泌尿外科杂志(电子版), 2024, 18(3): 202-207. [Huang H, Cheng BS, Huang J, et al. 2024 Annual Meeting of European Association of Urology: frontier exploration and future trends in prostate cancer research[J]. Chinese Journal of Endourology (Electronic Edition), 2024, 18(3): 202-207.] DOI: 10.3877/cma.j.issn.1674-3253. 2024.03.001.
5.Vaidyanathan K, Durning S, Wells L. Functional O-GlcNAc modifications: implications in molecular regulation and pathophysiology[J]. Crit Rev Biochem Mol Biol, 2014, 49(2): 140-163. DOI: 10.3109/10409238.2014.884535.
6.Le Minh G, Esquea EM, Young RG, et al. On a sugar high: role of O-GlcNAcylation in cancer[J]. J Biol Chem, 2023, 299(11): 105344. DOI: 10.1016/j.jbc.2023.105344.
7.Paneque A, Fortus H, Zheng J, et al. The hexosamine biosynthesis pathway: regulation and function[J]. Genes (Basel), 2023, 14(4): 933. DOI: 10.3390/genes14040933.
8.Marshall S, Bacote V, Traxinger RR. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance[J]. J Biol Chem, 1991, 266(8): 4706-4712. https://pubmed.ncbi.nlm.nih.gov/2002019/
9.Oki T, Yamazaki K, Kuromitsu J, et al. cDNA cloning and mapping of a novel subtype of glutamine:fructose-6-phosphate amidotransferase (GFAT2) in human and mouse[J]. Genomics, 1999, 57(2): 227-234. DOI: 10.1006/geno.1999.5785.
10.Yang S, Li G, Yin X, et al. Cancer-associated fibroblast expression of glutamine fructose-6-phosphate aminotransferase 2 (GFPT2) is a prognostic marker in gastric cancer[J]. J Pathol Clin Res, 2023, 9(5): 391-408. DOI: 10.1002/cjp2.333.
11.Zhang HR, Li TJ, Yu XJ, et al. The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion to regulate the tumor immune microenvironment in pancreatic cancer[J]. Cell Death Dis, 2024, 15(4): 244. DOI: 10.1038/s41419-024-06589-7.
12.Liu L, Pan Y, Ren X, et al. GFPT2 promotes metastasis and forms a positive feedback loop with p65 in colorectal cancer[J]. Am J Cancer Res, 2020, 10(8): 2510-2522. https://pubmed.ncbi.nlm.nih.gov/32905539/
13.Wang Q, Karvelsson ST, Kotronoulas A, et al. Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) is upregulated in breast epithelial-mesenchymal transition and responds to oxidative stress[J]. Mol Cell Proteomics, 2022, 21(2): 100185. DOI: 10.1016/j.mcpro.2021.100185.
14.Zhou L, Luo M, Cheng LJ, et al. Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) promotes the EMT of serous ovarian cancer by activating the hexosamine biosynthetic pathway to increase the nuclear location of β-catenin[J]. Pathol Res Pract, 2019, 215(12): 152681. DOI: 10.1016/j.prp.2019.152681.
15.Szymura SJ, Zaemes JP, Allison DF, et al. NF-κB upregulates glutamine-fructose-6-phosphate transaminase 2 to promote migration in non-small cell lung cancer[J]. Cell Commun Signal, 2019, 17(1): 24. DOI: 10.1186/s12964-019-0335-5.
16.Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis[J]. J Hematol Oncol, 2022, 15(1): 129. DOI: 10.1186/s13045-022-01347-8.
17.Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome[J]. Science, 2015, 347(6220): 1260419. DOI: 10.1126/science.1260419.
18.Sivakumar S, Lee JK, Moore JA, et al. Comprehensive genomic profiling and treatment patterns across ancestries in advanced prostate cancer: a large-scale retrospective analysis[J]. Lancet Digit Health, 2023, 5(6): e380-e389. DOI: 10.1016/s2589-7500(23)00053-5.
19.Fraser M, Sabelnykova VY, Yamaguchi TN, et al. Genomic hallmarks of localized, non-indolent prostate cancer[J]. Nature, 2017, 541(7637): 359-364. DOI: 10.1038/nature20788.
20.Lam C, Low JY, Tran PT, et al. The hexosamine biosynthetic pathway and cancer: current knowledge and future therapeutic strategies[J]. Cancer Lett, 2021, 503: 11-18. DOI: 10.1016/j.canlet.2021.01.010.
21.Akella NM, Ciraku L, Reginato MJ. Fueling the fire: emerging role of the hexosamine biosynthetic pathway in cancer[J]. BMC Biol, 2019, 17(1): 52. DOI: 10.1186/s12915-019-0671-3.
22.Chiaradonna F, Ricciardiello F, Palorini R. The nutrient-sensing hexosamine biosynthetic pathway as the hub of cancer metabolic rewiring[J]. Cells, 2018, 7(6): 53. DOI: 10.3390/cells7060053.
23.Itkonen HM, Minner S, Guldvik IJ, et al. O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells[J]. Cancer Res, 2013, 73(16): 5277-5287. DOI: 10.1158/0008-5472.Can-13-0549.
24.Zhang Y, Li J, Huang Y, et al. Improved antitumor activity against prostate cancer via synergistic targeting of Myc and GFAT-1[J]. Theranostics, 2023, 13(2): 578-595. DOI: 10.7150/thno.76614.
25.Kaushik AK, Shojaie A, Panzitt K, et al. Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer[J]. Nat Commun, 2016, 7: 11612. DOI: 10.1038/ncomms11612.