您的位置:山东大学 -> 科技期刊社 -> 《山东大学学报(医学版)》

山东大学学报(医学版) ›› 2015, Vol. 53 ›› Issue (9): 58-64.doi: 10.6040/j.issn.1671-7554.0.2015.415

• 临床医学 • 上一篇    下一篇

乌苯美司诱导肾癌细胞死亡的作用及机制

黄智龙1,2, 刘帅1, 王建伟1, 韩立平3, 王晓庆1, 李新1, 毕东滨1, 解放4, 牛志宏1   

  1. 1. 山东大学附属省立医院泌尿外科, 山东 济南 250021;
    2. 兰陵县人民医院泌尿科, 山东 兰陵 277700;
    3. 山东省警官总医院, 山东 济南 250002;
    4. 威海市立医院泌尿外科, 山东 威海 264200
  • 收稿日期:2015-04-05 出版日期:2015-09-10 发布日期:2015-09-10
  • 通讯作者: 牛志宏。E-mail:nzh1789@163.com E-mail:nzh1789@163.com
  • 基金资助:
    山东省自然科学基金(ZR2014HM111,ZR2014HP015)

Role and possible mechanism of autophagy in ubenimex-induced cell death of renal cell carcinoma

HUANG Zhilong1,2, LIU Shuai1, WANG Jianwei1, HAN Liping3, WANG Xiaoqing1, LI Xin1, BI Dongbin1, XIE Fang4, NIU Zhihong1   

  1. 1. Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China;
    2. Department of Urology Lanling County People's Hospital, Lanling 277700, Shandong, China;
    3. Shandong Police Hospital, Jinan 250002, Shandong, China;
    4. Department of Urology, Weihai Municipal Hospital, Weihai 264200, Shandong, China
  • Received:2015-04-05 Online:2015-09-10 Published:2015-09-10
  • Contact: 牛志宏。E-mail:nzh1789@163.com E-mail:nzh1789@163.com

摘要: 目的 观察乌苯美司对肾癌细胞增殖及死亡的影响并探讨其可能机制。方法 利用WST-8细胞增殖实验及细胞生长曲线检测乌苯美司对肾癌细胞增殖能力的影响;LDH释放实验检测乌苯美司对肾癌细胞死亡的影响;酶活性测定法及Western blotting研究乌苯美司诱导肾癌细胞APN活性及表达;Western blotting及免疫组化染色观察乌苯美司的作用靶点氨肽酶N(APN)/CD13在肾癌组织及正常组织中的表达。结果 乌苯美司不能降低肾癌细胞中APN的表达但是可以抑制其活性;乌苯美司可抑制肾癌细胞增殖及活力,诱导细胞自噬性死亡。结论 乌苯美司可抑制肾癌细胞增殖,并可通过诱导自噬引发肾癌细胞死亡。

关键词: 氨肽酶N, 细胞死亡, 肾癌, 乌苯美司, 自噬

Abstract: Objective To determine the effect of ubenimex on the proliferation of renal cell carcinoma cells and the possible mechanism. Methods WST-8 cell proliferation assay and cell growth curve were used to detect the proliferation of renal cell carcinoma cells. LDH cytotoxicity assay was used to detect the cell death of the renal cell carcinoma. Alanine-p-nitroanilido was used to detect the activity and expression of APN induced by ubenimex in renal cell carcinoma cell lines. Western blotting and immunohistochemical staining were used to detect the expression of APN/CD13 in tissues of normal kidney and renal cell carcinoma. Results Ubenimex could not reduce the express of APN in renal cell carcinoma but inhibit its activity. Ubenimex could inhibit the proliferation and activity of renal cell carcinoma cells, and induce autophagic cell death. Conclusion Ubenimex inhibits the proliferation of renal cell carcinoma cells and promotes levels of cell death in renal cell carcinoma cells via an autophagic mechanism.

Key words: Renal cell carcinoma, Autophagy, Aminopeptidase N, Ubenimex, Cell death

中图分类号: 

  • R692
[1] Su D, Stamatakis L, Singer EA, et al. Renal cell carcinoma: molecular biology and targeted therapy[J]. Curr Opin Oncol, 2014, 26(3):321-327.
[2] 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.
[3] Sugano O, Muto A, Kato M, et al. A case of renal cell carcinoma with lymph node metastasis keeping remission for five years by adjuvant immunotherapy with ubenimex[J]. Gan To Kagaku Ryoho, 2003, 30(10):1519-1522.
[4] Todde V, Veenhuis M, van der Klei IJ, et al. Autophagy: principles and significance in health and disease[J]. Biochim Biophys Acta, 2009, 1792(1):3-13.
[5] Bastola P, Stratton Y, Kellner E, et al. Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy[J]. PLoS One, 2013, 8(7):e70030.doi:10.1371/journal.pone.0070030.
[6] Zhang Q, Si S, Schoen S, et al. Folliculin deficient renal cancer cells show higher radiosensitivity through autophagic cell death[J]. J Urol, 2014, 191(6):1880-1888.
[7] Lin JF, Lin YC, Lin YH, et al. Zoledronic acid induces autophagic cell death in human prostate cancer cells[J]. J Urol, 2011, 185(4):1490-1496.
[8] Wickstrm M, Larsson R, Nygren P, et al. Aminopeptidase N (CD13) as a target for cancer chemotherapy[J]. Cancer Sci, 2011, 102(3):501-508.
[9] Mina-Osorio P. The moonlighting enzyme CD13: old and new functions to target[J]. Trends Mol Med, 2008, 14(8):361-371.
[10] Martin-Padura I, Marighetti P, Agliano A, et al. Residual dormant cancer stem-cell foci are responsible for tumor relapse after antiangiogenic metronomic therapy in hepatocellular carcinoma xenografts[J]. Lab Invest, 2012, 92(7):952-966.
[11] 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.
[12] 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.
[13] Ishii K, Usui S, Yamamoto H, et al. Decreases of metallothionein and aminopeptidase N in renal cancer tissues[J]. J Biochem, 2001, 129(2):253-258.
[14] 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.
[15] Kumar D, Shankar S, Srivastava RK. Rottlerin induces autophagy and apoptosis in prostate cancer stem cells via PI3K/Akt/mTOR signaling pathway[J]. Cancer Letters, 2014, 343(2):179-189.
[16] Chen RJ, Jha V, Singh SK, et al. Autophagy inhibition suppresses the tumorigenic potential of cancer stem cell enriched side population in bladder cancer[J]. Mol Nutr Food Res, 2014, 1842(11):2073-2086.
[17] 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.
[18] 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.
[19] Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1[J]. Nature, 1999, 402(6762):672-676.
[20] Mathew R, Kongara S, Beaudoin B, et al. Autophagy suppresses tumor progression by limiting chromosomal instability[J]. Genes Dev, 2007, 21(11):1367-1381.
[21] Karantza-Wadsworth V, Patel S, Kravchuk O, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis[J]. Genes Dev, 2007, 21(13):1621-1635.
[22] Tokuhara T, Hattori N, Ishida H, et al. Clinical significance of aminopeptidase N in non-smallcell lung cancer[J]. Clin Cancer Res, 2006, 12(13):3971-3978.
[23] Kawamura J, Shimada Y, Kitaichi H, et al. Clinicopathological significance of aminopeptidase N/CD13 expression in human gastric carcinoma[J]. Hepatogastroenterology, 2007, 54(73):36-40.
[24] Mawrin C, Wolke C, Haase D, et al. Reduced activity of CD13/aminopeptidase N (APN) in aggressive meningiomas is associated with increased levels of SPARC[J]. Brain Pathol, 2010, 20(1):200-210.
[25] Sørensen KD, Abildgaard MO, Haldrup C, et al. Prognostic significance of aberrantly silenced ANPEP expression in prostate cancer[J]. Br J Cancer, 2013, 108(2):420-428.
[1] 董萍,沈海涛,乔亚琴,路燕. 自噬在APAP肝损伤及肝再生过程中的调控作用[J]. 山东大学学报 (医学版), 2026, 64(5): 42-49.
[2] 陈杨,冯莹,卢晓,郑蓉. 半乳糖凝集素-3通过PI3K/Akt/mTOR通路促进巨噬细胞自噬分化[J]. 山东大学学报 (医学版), 2026, 64(4): 14-22.
[3] 张秋萍,朱慧志,吕川,夏咏琪,张秀. 基于生物信息学分析鉴定哮喘潜在的关键自噬和铁死亡相关基因[J]. 山东大学学报 (医学版), 2026, 64(1): 74-87.
[4] 宋彦威,付振美,徐静怡,马铭泽,孙琳琳. 弗林蛋白酶靶向同源性磷酸-张力蛋白调控线粒体自噬及肝纤维化进展[J]. 山东大学学报 (医学版), 2025, 63(4): 59-68.
[5] 刘爱静,李雁儒,高惠茹,段伟丽,李培龙,李娟,杜鲁涛,王传新. 自噬相关蛋白5在结肠癌中的表达及对结肠癌细胞迁移及侵袭能力的影响[J]. 山东大学学报 (医学版), 2024, 62(4): 14-23.
[6] 于丽,王弋嘉,杨勇,刘学焕,万雪花,包翠萍,苗蓓亮,李斯琪,李静,刘筠. 基于光学表面波技术探究具核梭杆菌介导的自噬与细胞折射率的关系[J]. 山东大学学报 (医学版), 2024, 62(10): 87-97.
[7] 郑荣慧,李攀,曹秀琴,贺瑞霞,陈民佳,陈海霞,杨志伟. SQSTM1蛋白在嗜肺军团菌感染RAW264.7细胞自噬中的作用机制[J]. 山东大学学报 (医学版), 2023, 61(6): 10-21.
[8] 任慧欣,郑茂金,韩文灿,王超群,周云,裴冬生. 过氧化氢通过调控自噬增强宫颈癌的放疗敏感性[J]. 山东大学学报 (医学版), 2023, 61(6): 22-28.
[9] 何静,严如根,武志红,李长忠. 消癥抑癌方对卵巢癌SKOV3细胞增殖、迁移的影响[J]. 山东大学学报 (医学版), 2023, 61(5): 1-10.
[10] 李娜,郭增丽,迟令懿,杨立卓,马志勇,付志婕. 甲醛对嗜酸性粒细胞EOL-1的急性损伤作用机制[J]. 山东大学学报 (医学版), 2022, 60(11): 54-62.
[11] 徐兵,李勇,刘明,刘永辉. 沉默PRRX1基因表达可增强前列腺癌耐药细胞株PC-3/DTX对多西他赛的敏感性[J]. 山东大学学报 (医学版), 2021, 59(6): 103-110.
[12] 张华宇,殷思源,刘健,马嘉旭,宋茹,曹国起,王一兵. 氧糖剥夺条件下培养表皮干细胞的定量蛋白质组学分析[J]. 山东大学学报 (医学版), 2021, 59(4): 17-27.
[13] 张小红,周云,杜秋莹,任慧欣,王超群. Atg7-siRNA通过调节精氨酸循环干扰食管癌ECA109细胞放疗敏感性[J]. 山东大学学报 (医学版), 2021, 59(4): 28-34.
[14] 索东阳,申飞,郭皓,刘力畅,杨惠敏,杨向东. Tim-3在药物性急性肾损伤动物模型中的表达及作用机制[J]. 山东大学学报 (医学版), 2020, 1(7): 1-6.
[15] 孙盼盼,赵旭,林小雯,傅志俭. 医用臭氧对大鼠骨关节炎软骨细胞中PPARγ及自噬水平表达的影响[J]. 山东大学学报 (医学版), 2020, 58(6): 14-21.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!