2025 02 v.34 81-86
La蛋白抑制剂Comp 1120通过53BP1途径增强卵巢癌细胞对卡铂的敏感性
基金项目(Foundation):
中华医学会临床药学分会2023年度临床药学科研基金（编号Z-2021-46-2101-2023）;
上海市青浦区卫生健康系统第五轮学科带头人培养计划（编号XD2023-10）
邮箱(Email):
tjfc2020@163.com;
DOI:
10.19577/j.1007-4406.2025.02.001
中文作者单位:
复旦大学附属妇产科医院;
摘要(Abstract):
目的 探讨La蛋白抑制剂Comp 1120在增强卵巢癌细胞对卡铂的敏感性中的作用机制。方法 使用A2780卵巢癌细胞株评估Comp 1120与卡铂联合使用的效果，特别关注P53结合蛋白1(53BP1)在此过程中的作用。采用Western blot、TUNEL实验和流式细胞术评估细胞凋亡情况。结果 Western blot分析显示，在卡铂与Comp 1120联合处理下，A2780卵巢癌细胞中促凋亡蛋白Caspase-3和BAX的表达显著上调（P <0.01），而抗凋亡蛋白Bcl-2的表达下调（P <0.01）。TUNEL实验和流式细胞术进一步证实，卡铂与Comp 1120联合使用显著促进了细胞凋亡（P <0.01）。所有实验结果均显示，这种促凋亡效应依赖于53BP1的表达；在53BP1基因沉默的细胞中，联合处理的促凋亡效应显著减弱（P <0.01），提示Comp 1120增强卡铂敏感性通过53BP1调控实现。结论 La蛋白抑制剂Comp 1120能有效增强卵巢癌细胞对卡铂的敏感性，其作用机制可能涉及对53BP1途径的调节。
关键词(KeyWords):
La蛋白;Comp 1120;卵巢癌;卡铂敏感性;53BP1
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参考文献
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[2] FUJIWARA K, MARKMAN M, MORGAN M, et al. Intraperitoneal carboplatin-based chemotherapy for epithelial ovarian cancer[J].Gynecol Oncol, 2005, 97(1):10.
[3] LOKICH J, ANDERSON N. Carboplatin versus cisplatin in solid tumors:an analysis of the literature[J]. Ann Oncol, 1998, 9(1):13.
[4] ORTIZ M, WABEL E, MITCHELL K, et al. Mechanisms of chemotherapy resistance in ovarian cancer[J]. Cancer Drug Resist, 2022, 5(2):304.
[5] XIA X Y, LI Z K, LI Y J, et al. LncRNA XIST promotes carboplatin resistance of ovarian cancer through activating autophagy via targeting miR-506-3p/FOXP1 axis[J]. J Gynecol Oncol, 2022,33(6):e81.
[6] EMBABY A, KUTZERA J, GEENEN J J, et al. WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53mutated ovarian cancer:a biomarker-enriched phase II study[J].Gynecol Oncol, 2023, 174:239.
[7] PIGNATA S, LORUSSO D, JOLY F, et al. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatinbased doublet alone in patients with platinum-sensitive ovarian cancer:a randomised, phase 3 trial[J]. Lancet Oncol, 2021,22(2):267.
[8] WETHINGTON S L, SHAH P D, MARTIN L, et al. Combination ATR(ceralasertib)and PARP(olaparib)inhibitor(CAPRI)trial in acquired PARP inhibitor-resistant homologous recombinationdeficient ovarian cancer[J]. Clin Cancer Res, 2023, 29(15):2800.
[9] SOMMER G, HEISE T. Role of the RNA-binding protein La in cancer pathobiology[J]. RNA Biol, 2021, 18(2):218.
[10] HOPKINS T G, MURA M, AL-ASHTAL H A, et al. The RNAbinding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer[J]. Nucleic Acids Res, 2016, 44(3):1227.
[11] HUANG X, ZHU J L, LI Y Y, et al. La protein regulates protein expression by binding with the mRNAs of target genes and participates the pathological process of ovarian cancer[J]. Front Oncol, 2022, 12:763480.
[12] LI Y Y, HUANG X, TANG J. Inhibiting the growth of ovarian cancer cells in vitro and in vivo by a small molecular inhibitor targeting La-RNA interactions[J]. Eur J Pharmacol, 2023, 940:175471.
[13] KABRANI E, SAHA T, DI VIRGILIO M. DNA repair and antibody diversification:the 53BP1 paradigm[J]. Trends Immunol, 2023,44(10):782.
[14] PANIER S, BOULTON S J. Double-strand break repair:53BP1comes into focus[J]. Nat Rev Mol Cell Biol, 2014, 15(1):7.
[15] BUNTING S F, CALLéN E, WONG N, et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks[J]. Cell, 2010, 141(2):243.
[16] SKULIMOWSKI M, BOURBONNAIS J, MALAQUIN N, et al.53BP1 mediates sensitivity to chemotherapy and is associated with poor clinical outcomes in high-grade serous ovarian cancer[J].bioRxiv, 2023:2023.09. 30.560286.
[17] ZHOU J B, KANG Y, CHEN L, et al. The drug-resistance mechanisms of five platinum-based antitumor agents[J]. Front Pharmacol, 2020, 11:343.
[18] MCMULLEN M, KARAKASIS K, MADARIAGA A, et al.Overcoming platinum and PARP-inhibitor resistance in ovarian cancer[J]. Cancers, 2020, 12(6):1607.
[19] ZHANG C Y, XU C, GAO X Y, et al. Platinum-based drugs for cancer therapy and anti-tumor strategies[J]. Theranostics, 2022,12(5):2115.
[20] LE SAUX O, RAY-COQUARD I, LABIDI-GALY S I. Challenges for immunotherapy for the treatment of platinum resistant ovarian cancer[J]. Semin Cancer Biol, 2021, 77:127.
[21] HUANG X, TANG J. Human La protein:an RNA-binding protein involved in ovarian cancer development and multidrug resistance[J]. Onco Targets Ther, 2020, 13:10721.
[22] FAN X T, ROSS D D, ARAKAWA H, et al. Impact of system L amino acid transporter 1(LAT1)on proliferation of human ovarian cancer cells:a possible target for combination therapy with antiproliferative aminopeptidase inhibitors[J]. Biochem Pharmacol,2010, 80(6):811.
[23] SOMMER G, ROSSA C, CHI A C, et al. Implication of RNAbinding protein La in proliferation, migration and invasion of lymph node-metastasized hypopharyngeal SCC cells[J]. PLoS One, 2011, 6(10):e25402.
基本信息:
DOI：10.19577/j.1007-4406.2025.02.001
中图分类号:R737.31
引用信息:
[1]李俊慜,朱佳蕾,汤静.La蛋白抑制剂Comp 1120通过53BP1途径增强卵巢癌细胞对卡铂的敏感性[J].中国临床药学杂志,2025,34(02):81-86.DOI:10.19577/j.1007-4406.2025.02.001.
基金信息:
中华医学会临床药学分会2023年度临床药学科研基金（编号Z-2021-46-2101-2023）; 上海市青浦区卫生健康系统第五轮学科带头人培养计划（编号XD2023-10）