糖代谢重编程在子宫内膜异位症中的研究进展

doi:10.12280/gjfckx.20230069

摘要/Abstract

摘要：

子宫内膜异位症是以疼痛和不孕为主要临床表现的慢性炎症性疾病，严重影响育龄期妇女的身心健康，需要长期管理。迄今为止，尚无有效治愈该疾病的方法。目前，已有多项研究证实子宫内膜异位症中存在糖代谢重编程现象，葡萄糖的大量摄入为能量代谢提供原料，糖酵解相关酶表达水平升高实现了细胞代谢从有氧氧化到糖酵解的转变，导致乳酸堆积，从而促进子宫内膜异位症的进展。糖代谢重编程的调控尚不完全清楚，多与缺氧微环境相关。这种代谢模式的转变是细胞存活和疾病进展的关键。可见，靶向葡萄糖、乳酸转运体、糖代谢相关酶及调控因子可能为子宫内膜异位症患者提供有益支持。

关键词: 子宫内膜异位症, 糖代谢重编程, 糖酵解, 瓦尔堡效应, 药物疗法

Abstract:

Endometriosis is a chronic inflammatory disease characterized by pain and infertility as the main clinical manifestations. It seriously affects the physical and mental health of women of reproductive age and requires long-term management. So far, there is no effective way to cure this disease. At present, several studies have confirmed that the existence of glucose metabolism reprogramming in endometriosis, where high glucose intake provides the raw material for energy metabolism. The increased expression level of glycolysis-related enzymes realizes the transformation of cell metabolism from aerobic oxidation to glycolysis, resulting in the accumulation of lactic acid and promoting the progress of endometriosis. The regulation of glucose metabolism reprogramming is not fully understood and is mostly related to the hypoxic microenvironment. This shift in metabolic patterns is crucial for cell survival and disease progression. It can be seen that targeting glucose, lactate transporters, glucose metabolism-related enzymes and regulatory factors can provide useful support for patients with endometriosis.

Key words: Endometriosis, Glucose metabolism reprogramming, Glycolysis, Warburg effect, Drug therapy

李尚瑾, 张冰, 丛珊珊, 赵绍杰. 糖代谢重编程在子宫内膜异位症中的研究进展[J]. 国际妇产科学杂志, 2023, 50(3): 246-250.

LI Shang-jin, ZHANG Bing, CONG Shan-shan, ZHAO Shao-jie. Research Progress of Glucose Metabolism Reprogramming in Endometriosis[J]. Journal of International Obstetrics and Gynecology, 2023, 50(3): 246-250.

图/表 2

参考文献 39

[1]	Saunders P, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects[J]. Cell, 2021, 184(11):2807-2824. doi: 10.1016/j.cell.2021.04.041. doi: 10.1016/j.cell.2021.04.041 pmid: 34048704
[2]	Vannuccini S, Clemenza S, Rossi M, et al. Hormonal treatments for endometriosis: The endocrine background[J]. Rev Endocr Metab Disord, 2022, 23(3):333-355. doi: 10.1007/s11154-021-09666-w. doi: 10.1007/s11154-021-09666-w
[3]	Cui Y, Li C, Sang F, et al. Natural products targeting glycolytic signaling pathways-an updated review on anti-cancer therapy[J]. Front Pharmacol, 2022, 13:1035882. doi: 10.3389/fphar.2022.1035882. doi: 10.3389/fphar.2022.1035882
[4]	Lu C, Qiao P, Fu R, et al. Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis[J]. Cell Death Dis, 2022, 13(9):790. doi: 10.1038/s41419-022-05241-6. doi: 10.1038/s41419-022-05241-6 pmid: 36109523
[5]	Lu J, Ling X, Liu L, et al. Emerging hallmarks of endometriosis metabolism: A promising target for the treatment of endometriosis[J]. Biochim Biophys Acta Mol Cell Res, 2023, 1870(1): 119381. doi: 10.1016/j.bbamcr.2022.119381. doi: 10.1016/j.bbamcr.2022.119381
[6]	Hou S, Lei S, Peng H, et al. Downregulating HK2 inhibits proliferation of endometrial stromal cells through a noncanonical pathway involving phosphorylation of signal transducer and activator of transcription 1 in endometriosis[J]. Biol Reprod, 2022, 107(2):488-499. doi: 10.1093/biolre/ioac081. doi: 10.1093/biolre/ioac081
[7]	Horne AW, Ahmad SF, Carter R, et al. Repurposing dichloroacetate for the treatment of women with endometriosis[J]. Proc Natl Acad Sci U S A, 2019, 116(51):25389-25391. doi: 10.1073/pnas.1916144116. doi: 10.1073/pnas.1916144116
[8]	Kobayashi H, Imanaka S. Understanding the molecular mechanisms of macrophage polarization and metabolic reprogramming in endometriosis: A narrative review[J]. Reprod Med Biol, 2022, 21(1):e12488. doi: 10.1002/rmb2.12488. doi: 10.1002/rmb2.12488
[9]	Kobayashi H, Shigetomi H, Imanaka S. Nonhormonal therapy for endometriosis based on energy metabolism regulation[J]. Reprod Fertil, 2021, 2(4):C42-C57. doi: 10.1530/RAF-21-0053. doi: 10.1530/RAF-21-0053 pmid: 35118411
[10]	McKinnon B, Bertschi D, Wotzkow C, et al. Glucose transporter expression in eutopic endometrial tissue and ectopic endometriotic lesions[J]. J Mol Endocrinol, 2014, 52(2):169-179. doi: 10.1530/JME-13-0194. doi: 10.1530/JME-13-0194 pmid: 24412827
[11]	Jones BC, Pohlmann PR, Clarke R, et al. Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux[J]. Cancer Metastasis Rev, 2022, 41(2):447-458. doi: 10.1007/s10555-022-10027-5. doi: 10.1007/s10555-022-10027-5
[12]	Yao Q, Jing G, Zhang X, et al. Cinnamic acid inhibits cell viability, invasion, and glycolysis in primary endometrial stromal cells by suppressing NF-κB-induced transcription of PKM2[J]. Biosci Rep, 2021 Sep 9:BSR20211828. doi: 10.1042/BSR20211828. doi: 10.1042/BSR20211828
[13]	Young VJ, Brown JK, Maybin J, et al. Transforming growth factor-β induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis[J]. J Clin Endocrinol Metab, 2014, 99(9):3450-3459. doi: 10.1210/jc.2014-1026. doi: 10.1210/jc.2014-1026 pmid: 24796928
[14]	Kocianova E, Piatrikova V, Golias T. Revisiting the Warburg Effect with Focus on Lactate[J]. Cancers(Basel), 2022, 14(24):6028. doi: 10.3390/cancers14246028. doi: 10.3390/cancers14246028
[15]	Zheng J, Dai Y, Lin X, et al. Hypoxia-induced lactate dehydrogenase A protects cells from apoptosis in endometriosis[J]. Mol Med Rep, 2021, 24(3):637. doi: 10.3892/mmr.2021.12276. doi: 10.3892/mmr.2021.12276
[16]	Atkins HM, Bharadwaj MS, O′Brien Cox A, et al. Endometrium and endometriosis tissue mitochondrial energy metabolism in a nonhuman primate model[J]. Reprod Biol Endocrinol, 2019, 17(1):70. doi: 10.1186/s12958-019-0513-8. doi: 10.1186/s12958-019-0513-8
[17]	Gou Y, Wang H, Wang T, et al. Ectopic endometriotic stromal cells-derived lactate induces M2 macrophage polarization via Mettl3/Trib1/ERK/STAT3 signalling pathway in endometriosis[J]. Immunology, 2023, 168(3):389-402. doi: 10.1111/imm.13574. doi: 10.1111/imm.13574
[18]	Contreras-Baeza Y, Sandoval PY, Alarcón R, et al. Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments[J]. J Biol Chem, 2019, 294(52):20135-20147. doi: 10.1074/jbc.RA119.009093. doi: 10.1074/jbc.RA119.009093 pmid: 31719150
[19]	Xin Q, Wang H, Li Q, et al. Lactylation: a Passing Fad or the Future of Posttranslational Modification[J]. Inflammation, 2022, 45(4):1419-1429. doi: 10.1007/s10753-022-01637-w. doi: 10.1007/s10753-022-01637-w
[20]	Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation[J]. Nature, 2019, 574(7779):575-580. doi: 10.1038/s41586-019-1678-1. doi: 10.1038/s41586-019-1678-1
[21]	Zhou Y, Jin Y, Wang Y, et al. Hypoxia activates the unfolded protein response signaling network: An adaptive mechanism for endometriosis[J]. Front Endocrinol(Lausanne), 2022, 13:945578. doi: 10.3389/fendo.2022.945578. doi: 10.3389/fendo.2022.945578
[22]	Young VJ, Ahmad SF, Brown JK, et al. ID2 mediates the transforming growth factor-β1-induced Warburg-like effect seen in the peritoneum of women with endometriosis[J]. Mol Hum Reprod, 2016, 22(9):648-654. doi: 10.1093/molehr/gaw045. doi: 10.1093/molehr/gaw045 pmid: 27385728
[23]	Wang Y, Xiu J, Yang T, et al. HSF1 promotes endometriosis development and glycolysis by up-regulating PFKFB3 expression[J]. Reprod Biol Endocrinol, 2021, 19(1):86. doi: 10.1186/s12958-021-00770-9. doi: 10.1186/s12958-021-00770-9
[24]	Ling X, Lu J, Wang X, et al. Ovarian tumor B1-mediated heat shock transcription factor 1 deubiquitination is critical for glycolysis and development of endometriosis[J]. iScience, 2022, 25(11):105363. doi: 10.1016/j.isci.2022.105363. doi: 10.1016/j.isci.2022.105363
[25]	Bahrami A, Ayen E, Razi M, et al. Effects of atorvastatin and resveratrol against the experimental endometriosis; evidence for glucose and monocarboxylate transporters, neoangiogenesis[J]. Life Sci, 2021, 272:119230. doi: 10.1016/j.lfs.2021.119230. doi: 10.1016/j.lfs.2021.119230
[26]	Zhou J, Ding ZM, Hardiman PJ. Understanding the Role of Gui-Zhi-Fu-Ling-Capsules (Chinese Medicine) for Treatment of Endometriosis in the Rat Model: Using NMR Based Metabolomics[J]. Evid Based Complement Alternat Med, 2018, 2018:9864963. doi: 10.1155/2018/9864963. doi: 10.1155/2018/9864963
[27]	Goldberg FW, Kettle JG, Lamont GM, et al. Discovery of Clinical Candidate AZD0095, a Selective Inhibitor of Monocarboxylate Transporter 4 (MCT4) for Oncology[J]. J Med Chem, 2023, 66(1):384-397. doi: 10.1021/acs.jmedchem.2c01342. doi: 10.1021/acs.jmedchem.2c01342
[28]	Wang H, Liang Z, Gou Y, et al. FTO-dependent N(6)-Methyladenosine regulates the progression of endometriosis via the ATG5/PKM2 Axis[J]. Cell Signal, 2022, 98:110406. doi: 10.1016/j.cellsig.2022.110406. doi: 10.1016/j.cellsig.2022.110406
[29]	Kim BS, Chung TW, Choi HJ, et al. Caesalpinia sappan induces apoptotic cell death in ectopic endometrial 12Z cells through suppressing pyruvate dehydrogenase kinase 1 expression[J]. Exp Ther Med, 2021, 21(4):357. doi: 10.3892/etm.2021.9788. doi: 10.3892/etm.2021.9788
[30]	Becker CM, Rohwer N, Funakoshi T, et al. 2-methoxyestradiol inhibits hypoxia-inducible factor-1α and suppresses growth of lesions in a mouse model of endometriosis[J]. Am J Pathol, 2008, 172(2):534-544. doi: 10.2353/ajpath.2008.061244. doi: 10.2353/ajpath.2008.061244
[31]	Pang C, Wu Z, Xu X, et al. Paeonol alleviates migration and invasion of endometrial stromal cells by reducing HIF-1α-regulated autophagy in endometriosis[J]. Front Biosci(Landmark Ed), 2021, 26(9):485-495. doi: 10.52586/4961. doi: 10.52586/4961
[32]	Ding J, Mei S, Cheng W, et al. Curcumin treats endometriosis in mice by the HIF signaling pathway[J]. Am J Transl Res, 2022, 14(4):2184-2198. pmid: 35559378
[33]	Sun Y, Wang Q, Wang M, et al. CHIP induces ubiquitination and degradation of HMGB1 to regulate glycolysis in ovarian endometriosis[J]. Cell Mol Life Sci, 2022, 80(1):13. doi: 10.1007/s00018-022-04637-z. doi: 10.1007/s00018-022-04637-z pmid: 36536161
[34]	Reckzeh ES, Waldmann H. Small-Molecule Inhibition of Glucose Transporters GLUT-1-4[J]. Chembiochem, 2020, 21(1/2):45-52. doi: 10.1002/cbic.201900544. doi: 10.1002/cbic.201900544
[35]	Viola A, Munari F, Sánchez-Rodríguez R, et al. The Metabolic Signature of Macrophage Responses[J]. Front Immunol, 2019, 10:1462. doi: 10.3389/fimmu.2019.01462. doi: 10.3389/fimmu.2019.01462 pmid: 31333642
[36]	Goswami KK, Banerjee S, Bose A, et al. Lactic acid in alternative polarization and function of macrophages in tumor microenvironment[J]. Hum Immunol, 2022, 83(5):409-417. doi: 10.1016/j.humimm.2022.02.007. doi: 10.1016/j.humimm.2022.02.007 pmid: 35300874
[37]	Kobayashi H, Kimura M, Maruyama S, et al. Revisiting estrogen-dependent signaling pathways in endometriosis: Potential targets for non-hormonal therapeutics[J]. Eur J Obstet Gynecol Reprod Biol, 2021, 258:103-110. doi: 10.1016/j.ejogrb.2020.12.044. doi: 10.1016/j.ejogrb.2020.12.044 pmid: 33421806
[38]	Leow HW, Koscielniak M, Williams L, et al. Dichloroacetate as a possible treatment for endometriosis-associated pain: a single-arm open-label exploratory clinical trial (EPiC)[J]. Pilot Feasibility Stud, 2021, 7(1):67. doi: 10.1186/s40814-021-00797-0. doi: 10.1186/s40814-021-00797-0 pmid: 33712086
[39]	Sharma D, Singh M, Rani R. Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics[J]. Semin Cancer Biol, 2022, 87:184-195. doi: 10.1016/j.semcancer.2022.11.007. doi: 10.1016/j.semcancer.2022.11.007 pmid: 36371026

药物	靶点	机制
抑制葡萄糖摄取与乳酸转运
阿托伐他汀和白藜芦醇	GLUT1和GLUT3	抑制糖酵解和新生血管形成^[25]
桂芝福灵胶囊	GLUT4	抑制高糖的摄入^[26]
AZD0095	MCT4	抑制乳酸的堆积^[27]（肿瘤中应用，EMs中未研究）
抑制糖代谢相关酶
3-溴丙酮酸	HK2	抑制糖酵解，减少子宫内膜间质细胞的迁移和增殖^[6]
PFKFB3抑制剂	PKM2	抑制糖酵解，调节线粒体功能^[28]
二氯乙酸盐（dichloroacetate，DCA）	PDK和PDH	涉及机制多，有前景，见下文详述
苏木心材	PDK1	抑制糖酵解；增加活性氧、下调膜电位致异位子宫内膜细胞凋亡^[29]
糖酵解相关调控因子
2-甲氧基雌二醇	HIF-1α	抑制HIF-1α下游蛋白，如GLUT1^[30]
芍药醇	HIF-1α	抑制HIF-1α诱导的病变^[31]
姜黄素	HIF通路	改善缺氧、降低炎症，下调HIF-1α表达^[32]
KRIBB11	HSF1	调控PFKFB3从而抑制糖酵解^[23]
YL-109	hsc70互作蛋白	hsc70互作蛋白诱导高迁移率族蛋白1泛素化和降解，抑制糖酵解^[33]

药物	靶点	机制
抑制葡萄糖摄取与乳酸转运
阿托伐他汀和白藜芦醇	GLUT1和GLUT3	抑制糖酵解和新生血管形成^[25]
桂芝福灵胶囊	GLUT4	抑制高糖的摄入^[26]
AZD0095	MCT4	抑制乳酸的堆积^[27]（肿瘤中应用，EMs中未研究）
抑制糖代谢相关酶
3-溴丙酮酸	HK2	抑制糖酵解，减少子宫内膜间质细胞的迁移和增殖^[6]
PFKFB3抑制剂	PKM2	抑制糖酵解，调节线粒体功能^[28]
二氯乙酸盐（dichloroacetate，DCA）	PDK和PDH	涉及机制多，有前景，见下文详述
苏木心材	PDK1	抑制糖酵解；增加活性氧、下调膜电位致异位子宫内膜细胞凋亡^[29]
糖酵解相关调控因子
2-甲氧基雌二醇	HIF-1α	抑制HIF-1α下游蛋白，如GLUT1^[30]
芍药醇	HIF-1α	抑制HIF-1α诱导的病变^[31]
姜黄素	HIF通路	改善缺氧、降低炎症，下调HIF-1α表达^[32]
KRIBB11	HSF1	调控PFKFB3从而抑制糖酵解^[23]
YL-109	hsc70互作蛋白	hsc70互作蛋白诱导高迁移率族蛋白1泛素化和降解，抑制糖酵解^[33]