雄激素阻断对膀胱癌UM-UC-3细胞自噬与凋亡的影响

doi:10.6040/j.issn.1671-7554.0.2017.251

摘要/Abstract

摘要： 目的探讨雄激素阻断对膀胱癌UM-UC-3细胞自噬与凋亡的影响。方法以双氢睾酮或比卡鲁胺激活或抑制UM-UC-3细胞AR信号通路,以雷帕霉素或氯喹进一步诱导或抑制UM-UC-3细胞自噬水平,根据以上不同处理条件进行相应分组。采用Hoechst染色、流式细胞仪和Western blotting检测UM-UC-3细胞凋亡;采用透射电镜、激光共聚焦显微镜和Western blotting检测UM-UC-3细胞自噬水平。结果雄激素去除或者AR阻断剂比卡鲁胺可以增强膀胱癌UM-UC-3细胞自噬和凋亡水平;雄激素阻断对UM-UC-3细胞的凋亡促进作用可以被氯喹抑制,并且可以被雷帕霉素增强。结论雄激素去除和AR阻断剂比卡鲁胺可以促进UM-UC-3细胞凋亡,这与其诱导细胞发生自噬相关。

关键词: 膀胱癌, 雄激素受体, 比卡鲁胺, 自噬, 凋亡

Abstract: Objective To explore the effect of androgen ablation and androgen receptor competitor biclutamide on autophagy and apoptosis in bladder cancer UM-UC-3 cells. Methods DHT and bicalutamide were respectively used to activate or inhibit androgen receptor signaling in UM-UC-3 cells. In addition, rapamycin and chloroquine were respectively used to induce or inhibit autophagy in UM-UC-3 cells. Hoechst staining, flow cytometry and Western blotting were used to observe the apoptotis. Autophagy flux was detected and quantified under transmission electronic microscope and confocal fluoresence microscope. Results Elevated autophagy and apoptosis levels were detected in UM-UC-3 cells after androgen ablation and androgen receptor competitor bicalutamide treatment. In addition, apoptosis induced by bicalutamide could be rescued by chloroquine and enhanced by rapamycin. Conclusion Androgen ablation and androgen receptor competitor bicalutamide promote apoptosis in UM-UC-3 cells due to autophagy induction.

Key words: Bladder cancer, Androgen receptor, Bicalutamide, Autophagy, Apoptosis

中图分类号:

R737.14

蒿魁元,赵圣,张宇,崔迪,荆翌峰,夏术阶,韩邦旻. 雄激素阻断对膀胱癌UM-UC-3细胞自噬与凋亡的影响[J]. 山东大学学报 (医学版), 2018, 56(3): 41-47.

HAO Kuiyuan, ZHAO Sheng, ZHANG Yu, CUI Di, JING Yifeng, XIA Shujie, HAN Bangmin. Effect of androgen blockade on autophagy and apoptosis in bladder cancer UM-UC-3 cells[J]. Journal of Shandong University (Health Sciences), 2018, 56(3): 41-47.

参考文献

[1] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2): 87-108.
[2] Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132.
[3] Wu JT, Han BM, Yu SQ, et al. Androgen receptor is a potential therapeutic target for bladder cancer[J]. Urology, 2010, 75(4): 820-827.
[4] Jing Y, Cui D, Guo W, et al. Activated androgen receptor promotes bladder cancer metastasis via Slug mediated epithelial-mesenchymal transition[J]. Cancer Lett, 2014, 348(1-2): 135-145.
[5] Shiota M, Takeuchi A, Yokomizo A, et al. Androgen receptor signaling regulates cell growth and vulnerability to Doxorubicin in bladder cancer[J]. J Urol, 2012, 188(1): 276-286.
[6] 崔玉朋, 吴吉涛, 冯帆, 等. 雄激素受体基因对人膀胱癌T24细胞黏附和侵袭力的影响[J]. 中华实验外科杂志, 2013, 30(5): 1007-1009. CUI Yupeng, WU Jitao, FENG Fan, et al. Effects of androgen receptor gene on adhesion and invasion of human bladder cancer T24 cells[J]. Chin J Exp Surg, 2013, 30(5): 1007-1009.
[7] Kawahara T, Ide H, Kashiwagi E, et al. Enzalutamide inhibits androgen receptor-positive bladder cancer cell growth[J]. Urol Oncol, 2016, 34(10): 432.e15-23.
[8] Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation[J]. Science, 2000, 290(5497): 1717-1721.
[9] 殷雷, 殷睿, 李文, 等. CYLD抑制自噬提高膀胱癌细胞吉西他滨化疗敏感性[J].山东大学学报(医学版), 2016, 54(11): 1-6. YIN Lei, YIN Rui, LI Wen, et al. CYLD improves bladder cancer gemcitabine chemosensitivity via suppressing autophagy[J]. Journal of Shandong University(Health Sciences), 2016, 54(11): 1-6.
[10] Li JR, Cheng CL, Yang CR, et al. Dual inhibitor of phosphoinositide 3-kinase/mammalian target of rapamycin NVP-BEZ235 effectively inhibits cisplatin-resistant urothelial cancer cell growth through autophagic flux[J]. Toxicol Lett, 2013, 220(3): 267-276.
[11] Miyamoto H, Yang Z, Chen YT, et al. Promotion of bladder cancer development and progression by androgen receptor signals[J]. J Natl Cancer Inst, 2007, 99(7): 558-568.
[12] Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy(3rd edition)[J]. Autophagy, 2016, 12(1): 1-222.
[13] Jitao W, Jinchen H, Qingzuo L, et al. Androgen receptor inducing bladder cancer progression by promoting an epithelial-mesenchymal transition[J]. Andrologia, 2014, 46(10): 1128-1133.
[14] Izumi K, Taguri M, Miyamoto H, et al. Androgen deprivation therapy prevents bladder cancer recurrence[J]. Oncotarget, 2014, 5(24): 12665-12674.
[15] Hsu JW, Hsu I, Xu D, et al. Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor[J]. Am J Pathol, 2013, 182(5): 1811-1820.
[16] Zhuang YH, Bläuer M, Tammela T, et al. Immunodetection of androgen receptor in human urinary bladder cancer[J]. Histopathology, 1997, 30(6): 556-562.
[17] Mir C, Shariat SF, van der Kwast TH,et al. Loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: a large multi-institutional study[J]. BJU Int, 2011, 108(1): 24-30.
[18] Mashhadi R, Pourmand G, Kosari F, et al. Role of steroid hormone receptors in formation and progression of bladder carcinoma: a case-control study[J]. Urol J, 2014, 11(6): 1968-1973.
[19] Bauckman KA, Mysorekar IU. Ferritinophagy drives uropathogenic Escherichia coli persistence in bladder epithelial cells[J]. Autophagy, 2016, 12(5): 850-863.
[20] Mariño G, Nisosantano M, Baehrecke EH, et al. Self-consumption: the interplay of autophagy and apoptosis[J]. Nat Rev Mol Cell Bio, 2014,15(2): 81-94.
[21] Ojha R, Singh SK, Bhattacharyya S, et al. Inhibition of grade dependent autophagy in urothelial carcinoma increases cell death under nutritional limiting condition and potentiates the cytotoxicity of chemotherapeutic agent[J]. J Urol, 2014, 191(6): 1889-1898.
[22] Lin YC, Lin JF, Wen SI, et al. Inhibition of high basal level of autophagy induces apoptosis in human bladder cancer cells[J]. J Urol, 2016, 195(4): 1126-1135.
[23] Huang YT, Cheng CC, Lin TC, et al. Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells[J]. Oncol Rep, 2014, 31(2): 771-780.
[24] Zeng LP, Hu ZM, Li K, et al. miR-222 attenuates cisplatin-induced cell death by targeting the PPP2R2A/Akt/mTOR Axis in bladder cancer cells[J]. J Cell Mol Med, 2016, 20(3): 559-567.
[25] Shi Y, Han JJ, Tennakoon JB, et al. Androgens promote prostate cancer cell growth through induction of autophagy[J]. Mol Endocrinol, 2013, 27(2): 280-295.
[26] Boutin B, Tajeddine N, Vandersmissen P, et al. Androgen deprivation and androgen receptor competition by bicalutamide induce autophagy of hormone-resistant prostate cancer cells and confer resistance to apoptosis[J]. Prostate, 2013, 73(10): 1090-1102.
[27] Jiang Q, Yeh S, Wang X, et al. Targeting androgen receptor leads to suppression of prostate cancer via induction of autophagy[J]. J Urol, 2012, 188(4): 1361-1368.

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