靶向脂代谢逆转头颈鳞癌治疗耐药性的研究进展

doi:10.13591/j.cnki.kqyx.2024.09.011

摘要/Abstract

摘要：

脂代谢重编程对头颈鳞癌发生发展、转移、耐药性形成至关重要。多种脂代谢关键酶在头颈鳞癌中表达上调,与癌症放化疗抵抗、预后不良密切相关。该文主要阐述头颈鳞癌中脂代谢的改变,从脂肪酸从头合成、脂肪酸氧化、甘油磷脂代谢以及甲羟戊酸与胆固醇合成途径四方面着手,探究脂代谢相关酶在头颈鳞癌中的表达异常及临床相关性、其对头颈鳞癌治疗耐药的影响及可能机制、已有的及潜在的靶向治疗策略。调整膳食结构辅助、多靶点联合用药、多种治疗方法联用可能是未来调控脂代谢、减少耐药、提高抗癌疗效的可行性策略。

关键词: 脂代谢, 头颈鳞癌, 治疗耐药, 癌症治疗

Abstract:

The reprogramming of lipid metabolism is a significant factor influencing various aspects of head and neck squamous cell carcinoma, including its occurrence, development, metastasis, and resistance to radio-chemotherapy. There is a considerable elevation in the expression levels of enzymes and genes related to lipid metabolism in tumor tissues compared to normal tissues. This up-regulation is associated with both treatment resistance and a poor prognosis. This review focuses mainly on alterations in lipid metabolism in head and neck squamous cell carcinoma. It systematically explores the atypical expression and clinical significance of lipid metabolism-related enzymes, evaluates their influence on treatment resistance, elucidates the underlying mechanisms of this resistance, and discusses current and potential targeted therapeutic approaches. The comprehensive analysis comprises four pivotal aspects: de novo lipogenesis, fatty acid oxidation, glycerophospholipids metabolism, and mevalonate and cholesterol synthesis pathways. Feasible strategies, such as the adjustment of dietary structure, the administration of multi-target drugs, and the utilization of combination treatment therapies, are deliberated as potential interventions to modulate lipid metabolism, reverse treatment resistance, and enhance the efficacy of anti-cancer treatments.

Key words: lipid metabolism, head and neck squamous cell carcinoma, treatment resistance, cancer therapy

中图分类号:

R739.8

王盼, 吕炯, 朱慧勇. 靶向脂代谢逆转头颈鳞癌治疗耐药性的研究进展[J]. 口腔医学, 2024, 44(9): 705-709.

WANG Pan, LYU Jiong, ZHU Huiyong. Research progress of reversing treatment resistance in head and neck squamous cell carcinoma by targeting lipid metabolism[J]. Stomatology, 2024, 44(9): 705-709.

参考文献 41

[1]	Fasano M, D’Onofrio I, Belfiore MP, et al. Head and neck squamous cell carcinoma in elderly patients: Role of radiotherapy and chemotherapy[J]. Cancers, 2022, 14(3): 472.
[2]	Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023[J]. CA A Cancer J Clinicians, 2023, 73(1): 17-48.
[3]	Yuan ZC, Huang JT, Teh BM, et al. Exploration of a predictive model based on genes associated with fatty acid metabolism and clinical treatment for head and neck squamous cell carcinoma[J]. J Clin Lab Anal, 2022, 36(11): e24722.
[4]	Li LY, Yang Q, Jiang YY, et al. Interplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer[J]. Nat Commun, 2021, 12(1): 4362.
[5]	Tan M, Lin XY, Chen HY, et al. Sterol regulatory element binding transcription factor 1 promotes proliferation and migration in head and neck squamous cell carcinoma[J]. Peer J, 2023, 11: e15203.
[6]	Li K, Zhang CC, Chen L, et al. The role of acetyl-coA carboxylase2 in head and neck squamous cell carcinoma[J]. Peer J, 2019, 7: e7037.
[7]	Göttgens EL, van den Heuvel CN, de Jong MC, et al. ACLY (ATP citrate lyase) mediates radioresistance in head and neck squamous cell carcinomas and is a novel predictive radiotherapy biomarker[J]. Cancers, 2019, 11(12): 1971.
[8]	Kao YC, Lee SW, Lin LC, et al. Fatty acid synthase overexpression confers an independent prognosticator and associates with radiation resistance in nasopharyngeal carcinoma[J]. Tumour Biol, 2013, 34(2): 759-768.
[9]	Aquino IG, Bastos DC, Cuadra-Zelaya FJM, et al. Anticancer properties of the fatty acid synthase inhibitor TVB-3166 on oral squamous cell carcinoma cell lines[J]. Arch Oral Biol, 2020, 113: 104707.
[10]	Chen JY, Zhang F, Ren XS, et al. Targeting fatty acid synthase sensitizes human nasopharyngeal carcinoma cells to radiation via downregulating frizzled class receptor 10[J]. Cancer Biol Med, 2020, 17(3): 740-752.
[11]	Agostini M, Almeida LY, Bastos DC, et al. The fatty acid synthase inhibitor orlistat reduces the growth and metastasis of orthotopic tongue oral squamous cell carcinomas[J]. Mol Cancer Ther, 2014, 13(3): 585-595. doi: 10.1158/1535-7163.MCT-12-1136 pmid: 24362464
[12]	Almeida LY, Moreira FDS, Santos GASD, et al. FASN inhibition sensitizes metastatic OSCC cells to cisplatin and paclitaxel by downregulating cyclin B1[J]. Oral Dis, 2023, 29(2): 649-660.
[13]	Jain P, Nattakom M, Holowka D, et al. Runx1 role in epithelial and cancer cell proliferation implicates lipid metabolism and Scd1 and Soat1 activity[J]. Stem Cells, 2018, 36(10): 1603-1616. doi: 10.1002/stem.2868 pmid: 29938858
[14]	Nanjappa V, Renuse S, Sathe GJ, et al. Chronic exposure to chewing tobacco selects for overexpression of stearoyl-CoA desaturase in normal oral keratinocytes[J]. Cancer Biol Ther, 2015, 16(11): 1593-1603. doi: 10.1080/15384047.2015.1078022 pmid: 26391970
[15]	Min JY, Kim DH. Stearoyl-CoA desaturase 1 as a therapeutic biomarker: Focusing on cancer stem cells[J]. Int J Mol Sci, 2023, 24(10): 8951.
[16]	Schminke B, Shomroni O, Salinas G, et al. Prognostic factor identification by screening changes in differentially expressed genes in oral squamous cell carcinoma[J]. Oral Dis, 2023, 29(1): 116-127.
[17]	Tracz-Gaszewska Z, Dobrzyn P. Stearoyl-CoA desaturase 1 as a therapeutic target for thetreatment of cancer[J]. Cancers, 2019, 11(7): 948.
[18]	Luo M, Liu YQ, Zhang H, et al. Overexpression of carnitine palmitoyltransferase 1A promotes mitochondrial fusion and differentiation of glioblastoma stem cells[J]. Lab Invest, 2022, 102(7): 722-730.
[19]	Schlaepfer IR, Joshi M. CPT1A-mediated fat oxidation, mechanisms, and therapeutic potential[J]. Endocrinology, 2020, 161(2): bqz046.
[20]	Chen YX, Zhou YY, Han FW, et al. A novel miR-1291-ERRα-CPT1C axis modulates tumor cell proliferation, metabolism and tumorigenesis[J]. Theranostics, 2020, 10(16): 7193-7210. doi: 10.7150/thno.44877 pmid: 32641987
[21]	Du QQ, Tan ZQ, Shi F, et al. PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation[J]. Cancer Sci, 2019, 110(6): 2050-2062.
[22]	Moody L, Xu GB, Chen H, et al. Epigenetic regulation of carnitine palmitoyltransferase 1 (Cpt1a) by high fat diet[J]. Biochim Biophys Acta Gene Regul Mech, 2019, 1862(2): 141-152.
[23]	Tan ZQ, Xiao LB, Tang M, et al. Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy[J]. Theranostics, 2018, 8(9): 2329-2347. doi: 10.7150/thno.21451 pmid: 29721083
[24]	Holubarsch CJF, Rohrbach M, Karrasch M, et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: The ERGO (etomoxir for the recovery of glucose oxidation) study[J]. Clin Sci, 2007, 113(4): 205-212.
[25]	Fujiwara N, Nakagawa H, Enooku K, et al. CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity[J]. Gut, 2018, 67(8): 1493-1504. doi: 10.1136/gutjnl-2017-315193 pmid: 29437870
[26]	Calzada E, Onguka O, Claypool SM. Phosphatidylethanolamine metabolism in health and disease[J]. Int Rev Cell Mol Biol, 2016, 321: 29-88. doi: 10.1016/bs.ircmb.2015.10.001 pmid: 26811286
[27]	Uchiyama Y, Hayasaka T, Masaki N, et al. Imaging mass spectrometry distinguished the cancer and stromal regions of oral squamous cell carcinoma by visualizing phosphatidylcholine (16: 0/16: 1) and phosphatidylcholine (18: 1/20: 4)[J]. Anal Bioanal Chem, 2014, 406(5): 1307-1316.
[28]	Yang XH, Song XW, Yang XD, et al. Big cohort metabolomic profiling of serum for oral squamous cell carcinoma screening and diagnosis[J]. Natural Sciences, 2022, 2(1): e20210071.
[29]	Wang YH, Zhang XX, Wang S, et al. Identification of metabolism-associated biomarkers for early and precise diagnosis of oral squamous cell carcinoma[J]. Biomolecules, 2022, 12(3): 400.
[30]	Yang T, Hui RT, Nouws J, et al. Untargeted metabolomics analysis of esophageal squamous cell cancer progression[J]. J Transl Med, 2022, 20(1): 127.
[31]	Liu F, Wu Y, Liu J, et al. A miR-205-LPCAT1 axis contributes to proliferation and progression in multiple cancers[J]. Biochem Biophys Res Commun, 2020, 527(2): 474-480.
[32]	Shida-Sakazume T, Endo-Sakamoto Y, Unozawa M, et al. Lysophosphatidylcholine acyltransferase1 overexpression promotes oral squamous cell carcinoma progression via enhanced biosynthesis of platelet-activating factor[J]. PLoS One, 2015, 10(3): e0120143.
[33]	Zhang HY, Zheng YQ. LPCAT1 is transcriptionally regulated by FOXA1 to promote breast cancer progression and paclitaxel resistance[J]. Oncol Lett, 2023, 25(4): 134.
[34]	Tao MY, Luo J, Gu T, et al. LPCAT1 reprogramming cholesterol metabolism promotes the progression of esophageal squamous cell carcinoma[J]. Cell Death Dis, 2021, 12(9): 845.
[35]	Xue LY, Qi HY, Zhang H, et al. Targeting SREBP-2-regulated mevalonate metabolism for cancer therapy[J]. Front Oncol, 2020, 10: 1510. doi: 10.3389/fonc.2020.01510 pmid: 32974183
[36]	Tilija Pun N, Jeong CH. Statin as a potential chemotherapeutic agent: Current updates as a monotherapy, combination therapy, and treatment for anti-cancer drug resistance[J]. Pharmaceuticals, 2021, 14(5): 470.
[37]	Kansal V, Burnham AJ, Kinney BLC, et al. Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models[J]. J Immunother Cancer, 2023, 11(1): e005940.
[38]	Fernandez KA, Allen P, Campbell M, et al. Atorvastatin is associated with reduced cisplatin-induced hearing loss[J]. J Clin Invest, 2021, 131(1): e142616.
[39]	Ricco N, Flor A, Wolfgeher D, et al. Mevalonate pathway activity as a determinant of radiation sensitivity in head and neck cancer[J]. Mol Oncol, 2019, 13(9): 1927-1943. doi: 10.1002/1878-0261.12535 pmid: 31225926
[40]	Zhao XY, Guo B, Sun WJ, et al. Targeting squalene epoxidase confers metabolic vulnerability and overcomes chemoresistance in HNSCC[J]. Adv Sci, 2023, 10(27): e2206878.
[41]	Liu Y, Fang LJ, Liu WX. High SQLE expression and gene amplification correlates with poor prognosis in head and neck squamous cell carcinoma[J]. Cancer Manag Res, 2021, 13: 4709-4723. doi: 10.2147/CMAR.S305719 pmid: 34163246