山东大学学报 (医学版) ›› 2019, Vol. 57 ›› Issue (12): 46-51.doi: 10.6040/j.issn.1671-7554.0.2019.886
• • 上一篇
关红卫,李娟,孙锐,刘婕,李长忠
GUAN Hongwei, LI Juan, SUN Rui, LIU Jie, LI Changzhong
摘要: 目的 研究乌苯美司对卵巢癌A2780细胞增殖、细胞周期、凋亡和自噬以及迁移和侵袭能力的影响,探讨可能的作用机制。 方法 CCK-8实验检测乌苯美司对A2780细胞增殖的影响;Transwell实验检测乌苯美司对A2780细胞迁移及侵袭能力的影响;流式细胞术检测乌苯美司对A2780细胞凋亡和细胞周期的影响;Western blotting检测APN、AKT、p-AKT、LC3B、p62表达水平的变化。 结果 (1)乌苯美司能够抑制A2780细胞的增殖(F浓度=812.56,P<0.001;F时间=8.58,P=0.010;F交互=4.00,P=0.027)、迁移(t=56.9,P<0.001)和侵袭(t=11.8,P<0.001)、导致G2/M期细胞比例增高(t=7.9,P=0.016),G1期细胞比例减少(t=14.8,P=0.005),发生G2/M细胞周期阻滞。(2)乌苯美司能够诱导A2780细胞凋亡(P=0.002),且联合应用AKT抑制剂后诱导细胞凋亡的作用增强(P=0.007)。(3)乌苯美司可以导致APN表达降低,p-AKT、LC3-B和p62表达增加。 结论 乌苯美司可能是卵巢癌的一种治疗方法或者辅助治疗方法,与AKT抑制剂联用能够增强其治疗效果。
中图分类号:
[1] Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. [2] Jin H, Yu Y, Zhang T, et al. Snail is critical for tumor growth and metastasis of ovarian carcinoma[J]. Int J Cancer, 2010, 126(9): 2102-2111. [3] Cannistra SA. Cancer of the ovary[J]. New Engl J Med, 2004, 351(24): 2519-2529. [4] Ffrench B, Gasch C, O’Leary JJ, et al. Developing ovarian cancer stem cell models: laying the pipeline from discovery to clinical intervention[J]. Mol Cancer, 2014, 13: 262. doi: 10.1186/1476-4598-13-262. [5] Liu S, Xie F, Wang H, et al. Ubenimex inhibits cell proliferation, migration and invasion in renal cell carcinoma: the effect is autophagy-associated[J]. Oncol Rep, 2015, 33(3): 1372-1380. [6] Hitzerd SM, verbrugge SE, Ossenkoppele G, et al. Positioning of aminopeptidase inhibitors in next generation cancer therapy[J]. Amino Acids, 2014, 46(4): 793-808. [7] Wickstr(¨overo)m M, Larsson R, Nygren P, et al. Aminopeptidase N(CD13)as a target for cancer chemotherapy[J]. Cancer Sci, 2011, 102(3): 501-508. [8] Wakita A, Ohtake S, Takada S, et al. Randomized comparison of fixed-schedule versus response-oriented individualized induction therapy and use of ubenimex during and after consolidation therapy for elderly patients with acute myeloid leukemia: the JALSG GML200 Study[J]. Int J Hematol, 2012, 96(1): 84-93. [9] Ichinose Y, Genka K, Koike T, et al. NK421 Lung Cancer Surgery Group: randomized double-blind placebo-controlled trial of bestatin in patients with resected stage I squamous-cell lung carcinoma[J]. J Natl Cancer Inst, 2003, 95(8): 605-610. [10] Xu JW, Li CG, Huang XE, et al. Ubenimex capsule improves general performance and chemotherapy related toxicity in advanced gastric cancer cases[J]. Asian Pac J Cancer Prev, 2011, 12(4): 985-987. [11] Tsukamoto H, Shibata K, Kajiyama H, et al. Aminopeptidase N(APN)/CD13 inhibitor, Ubenimex, enhances radiation sensitivity in human cervical cancer[J]. BMC Cancer, 2008, 8:74. doi: 10.1186/1471-2407-8-74. [12] Tang Z, Li C, Kang B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses[J]. Nucleic Acids Res, 2017, 45(W1): W98-W102. [13] Terauchi M, Kajiyama H, Shibata K, et al. Inhibition of APN/CD13 leads to suppressed progressive potential in ovarian carcinoma cells[J]. BMC Cancer, 2007, 7: 140. [14] 路金枝,陈爱平.顺铂联合乌苯美司对卵巢癌SKOV3细胞体外生长的作用[J].山东医药, 2012, 52(25): 50-52. [15] Wang X, Liu Y, Wu R, et al. Role of ubenimex as an anticancer drug and its synergistic effect with akt inhibitor in human A375 and A2058 cells[J]. Onco Targets Ther, 2018, 11: 943-953. doi: 10.2147/OTT.S157480. [16] Aozuka Y, Koizumi K, Saitoh Y, et al. Anti-tumor angiogenesis effect of aminopeptidase inhibitor bestatin against B16-BL6 melanoma cells orthotopically implanted into syngeneic mice[J]. Cancer Lett, 2004, 216(1): 35-42. [17] Ishii K, Usui S, Sugimura Y, et al. Inhibition of aminopeptidase N(AP-N)and urokinase-type plasminogen activator(uPA)by zinc suppresses the invasion activity in human urological cancer cells[J]. Biol Pharm Bull, 2001, 24(3): 226-230. [18] Malaguarnera L. Implication of apoptosis regulation in tumorigenesis[J]. Cancer Metastasis Rev, 2004, 23(3-4): 367-387. [19] Han L, Zhang Y, Liu S, et al. Autophagy flux inhibition, G2/M cell cycle arrest and apoptosis induction by ubenimex in glioma cell lines[J]. Oncotarget, 2017, 8(64): 107730-107743. [20] Klionsky DJ. Autophagy from phenomenology to molecular understanding in less than a decade[J]. Nat Rev Mol Cell Biol, 2007, 8(11): 931-937. [21] Eum KH, Lee M. Crosstalk between autophagy and apoptosis in the regulation of paclitaxel-induced cell death in v-Ha-ras-transformed fibroblasts[J]. Mol Cell Biochem, 2011, 348(1-2): 61-68. [22] Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research[J]. Cell, 2010, 140(3): 313-326. [23] Han L, Zhao Q, Liang X, et al. Ubenimex enhances Brd4 inhibition by suppressing HEXIM1 autophagic degradation and suppressing the Akt pathway in glioma cells[J]. Oncotarget, 2017, 8(28): 45643-45655. [24] Krajarng A, Chulasiri M, Watanapokasin R. Etlingera elatior Extract promotes cell death in B16 melanoma cells via down-regulation of ERK and Akt signaling pathways[J]. BMC Complement Altern Med, 2017, 17(1):415. doi: 10.1186/s12906-017-1921-y. [25] Díaz M, González R, Plano D, et al. A diphenyldiselenide derivative induces autophagy via JNK in HTB-54 lung cancer cells[J]. J Cell Mol Med, 2018, 22(1): 289-301. [26] Tang R, Xu X, Yang W, et al. MED27 promotes melanoma growth by targeting AKT/MAPK and NF-κB/iNOS signaling pathways[J]. Cancer Lett, 2016, 373(1): 77-87. [27] Wu J, Hu G, Dong Y, et al. Matrine induces Akt/mTOR signalling inhibition-mediated autophagy and apoptosis in acute myeloid leukaemia cells[J]. J Cell Mol Med, 2017, 21(6): 1171-1181. [28] Wang C, Zhang X, Teng Z, et al. Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice[J]. Eur J Pharmacol, 2014, 740: 312-320. doi: 10.1016/j.ejphar.2014.06.051. |
[1] | 张士宝 刘庆勇 阮喜云 陈杰 张建军 李宗武 杨广笑 王全颖. NT4-SAC-HA2-TAT融合基因表达载体的构建及鉴定[J]. 山东大学学报(医学版), 2209, 47(6): 15-19. |
[2] | 王晓磊 张海涛 张辉 郭成浩. 舒血宁注射液对高碘致培养血管内皮细胞损伤的保护作用[J]. 山东大学学报(医学版), 2209, 47(6): 38-. |
[3] | 鹿向东 杨伟 徐广明 曲元明. 脑膜瘤中PPAR-γ的表达及曲格列酮对脑膜瘤培养细胞生长的影响[J]. 山东大学学报(医学版), 2209, 47(6): 65-. |
[4] | 赵舸,邹存华,宋冬冬,赵淑萍. 丹参酮IIA对子宫内膜癌细胞增殖与凋亡的影响[J]. 山东大学学报 (医学版), 2022, 60(9): 53-58. |
[5] | 张振伟,李佳,陈克明. IGF2BP2/m6A/ITGA5信号轴调控肾透明细胞增殖和迁移[J]. 山东大学学报 (医学版), 2022, 60(9): 74-84. |
[6] | 张艺馨,赵玉立,封丽. 超声特征及术前CA-125联合对51例卵巢交界性及Ⅰ期恶性肿瘤的鉴别诊断[J]. 山东大学学报 (医学版), 2022, 60(7): 104-109. |
[7] | 孙丽娜,杜晓晓,张红娟,孟金来. 人类白细胞抗原G调控蜕膜自然杀伤细胞促进滋养细胞侵袭[J]. 山东大学学报 (医学版), 2022, 60(6): 41-45. |
[8] | 刘敏,张玉超,马小莉,刘昕宇,孙露,左丹,刘元涛. 孤核受体NR4A1在H2O2诱导小鼠肾脏足细胞损伤中的作用[J]. 山东大学学报 (医学版), 2022, 60(5): 16-21. |
[9] | 申晓畅,孙一卿,颜磊,赵兴波. 芳基烃受体核转位因子样蛋白2在子宫内膜癌中的表达[J]. 山东大学学报 (医学版), 2022, 60(5): 74-80. |
[10] | 陈兆波,方敏,薛浩然,刘春艳. 去泛素化酶USP35促进非小细胞肺癌细胞迁移和侵袭[J]. 山东大学学报 (医学版), 2022, 60(4): 30-37. |
[11] | 钟黎黎,盛莹,郭江虹,阳双健,何宜静. LncRNA-UCA1通过靶向调控miR-182-5p对滋养细胞侵袭与转移的影响[J]. 山东大学学报 (医学版), 2022, 60(3): 76-82. |
[12] | 宋甜,付琳琳,王秋敏,杨晓,王莹,边月红,石玉华. 脂肪酸转运蛋白1在多囊卵巢综合征患者颗粒细胞中的表达[J]. 山东大学学报 (医学版), 2022, 60(2): 22-26. |
[13] | 亓梦雨,周敏然,孙洺山,李世洁,陈春燕. T大颗粒淋巴细胞白血病合并原发性骨髓纤维化1例[J]. 山东大学学报 (医学版), 2022, 60(2): 118-120. |
[14] | 李卉,姜朝阳,刘岩,张曼. 组蛋白去乙酰化酶SIRT1调控氧化低密度脂蛋白诱导巨噬细胞凋亡的表达[J]. 山东大学学报 (医学版), 2022, 60(1): 6-12. |
[15] | 哈春芳,李茹月. 卵巢癌耐药机制与靶向治疗策略的研究进展[J]. 山东大学学报 (医学版), 2021, 59(9): 117-123. |
|