去甲斑螯素诱导的PP2A的抑制对提高CNE1的放射活性的影响

吕鹏, 许大彬, 吴绮峰, 王越, 王爱平, 王峥, 曾益新, 庄正平

中国药学杂志 ›› 2016, Vol. 51 ›› Issue (18) : 1579-1585.

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中国药学杂志
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中国药学杂志 ›› 2016, Vol. 51 ›› Issue (18) : 1579-1585. DOI: 10.11669/cpj.2016.18.009
论著

去甲斑螯素诱导的PP2A的抑制对提高CNE1的放射活性的影响

  • 吕鹏1,2,4,5,7, 许大彬3*, 吴绮峰4, 王越5, 王爱平2, 王峥4, 曾益新4, 庄正平6
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Research of Protein Phosphatase 2A Inhibition by Norcantharidin on Radiosensitivity Enhancement of Nasopharyngeal Carcinoma CNE1

  • Lü Peng1,2,4,5,7, XU Da-bin3*, WU Qi-feng4, WANG Yue5, WANG Ai-ping2, WANG Zheng4, ZENG Yi-xin4, ZHUANG Zheng-ping6
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摘要

目的 研究去甲斑螯素所诱导的蛋白磷酸酶2A(PP2A)的抑制对鼻咽癌细胞系CNE1及其裸鼠移植瘤放射增敏的影响。方法 采用免疫共沉淀、流式细胞术等方法探讨去甲斑螯素(40 μmol·L-1)或(和)放射处理(8 Gy)对鼻咽癌细胞CNE1及其裸鼠移植瘤 PP2A活性、细胞周期、凋亡的影响情况,研究去甲斑螯素抑制PP2A后于放射作用下所诱导的鼻咽癌细胞CNE1及其移植瘤组织生物学现象的变化。结果 去甲斑螯素协同放射处理相比较其他各处理组,G2/M期细胞显著聚集增多(45.71±2.015)%,凋亡率也明显提高(75.63±6.11)%,裸鼠移植瘤抑瘤率达到87.64%。结论 PP2A的抑制显著诱导鼻炎癌细胞的凋亡与延迟移植瘤的生长,其很有可能成为提高鼻咽癌放射增敏作用的新靶点。

Abstract

OBJECTIVE To investigate the radiosensitizing effect of PP2A inhibition on nasopharyngeal carcinoma cells and its xenografts.METHODS Co-immunoprecipitation and flow cytometry were used to examine PP2A activity, cell cycle analysis and apoptosis of CNE1 and its xenografts, in order to explore the effect of radiosensitization in CNE1 cells. RESULTS Cell cycle distribution and apoptosis were measured by flow cytometry 24 h after treatment. The combination of 8 Gy and 40 μmol·L-1 norcantharidin produced significantly accumulation of cells in G2/M-phase(45.71±2.015)% and more apoptosis(75.63±6.11)% in CNE1 cell lines compared with norcantharidin alone and to radiation alone. norcantharidin in combination with radiation produced the greatest effects on tumor growth slowing and decreasing tumor weight by 87.64% relative to vehicle in CNE1 xenografts. Our data demonstrate that inhibition of PP2A with radiation significantly sensitizes nasopharyngeal carcinoma cell lines in vitro and in vivo.CONCLUSION The inhibition of PP2A with norcantharidin inhibited xenograft growth obviously.Our RESULTS support further exploration of PP2A inhibition as part of radiotherapy regimens for NPC and potentially other solid tumors.

关键词

蛋白磷酸酶2A / 放射敏化 / 鼻咽癌 / 去甲斑螯素

Key words

protein phosphatase 2A / radiosensitizion / nasopharyngeal carcinoma / norcantharidin

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吕鹏, 许大彬, 吴绮峰, 王越, 王爱平, 王峥, 曾益新, 庄正平. 去甲斑螯素诱导的PP2A的抑制对提高CNE1的放射活性的影响[J]. 中国药学杂志, 2016, 51(18): 1579-1585 https://doi.org/10.11669/cpj.2016.18.009
Lü Peng, XU Da-bin, WU Qi-feng, WANG Yue, WANG Ai-ping, WANG Zheng, ZENG Yi-xin, ZHUANG Zheng-ping. Research of Protein Phosphatase 2A Inhibition by Norcantharidin on Radiosensitivity Enhancement of Nasopharyngeal Carcinoma CNE1[J]. Chinese Pharmaceutical Journal, 2016, 51(18): 1579-1585 https://doi.org/10.11669/cpj.2016.18.009
中图分类号： R969   

参考文献

[1] LI X P. Otolaryngology (耳鼻咽喉科学)[M]. Beijing:Peking University Medical Press,2003:133.
[2] HUANG Z Y,WANG J B,KONG W J.Practice of Otorhinolaryngology Head and Neck Surgery (实用耳鼻咽喉头颈外科学)[M]. Beijing:People's Medical Publishing House,2011:342.
[3] YU M C, YUAN J M. Epidemiology of nasopharyngeal carcinoma[J]. J Semin Cancer Biol, 2002, 12(6): 421-429.
[4] VOKES E E, LIEBOWITZ D N, WEICHSEL R R. Nasopharyngeal carcinoma[J].J Lancet, 1997, 350 (9084): 1087-1091.
[5] SONTAG E. Protein phosphatase 2A:the trojan horse of cellular signaling[J]. Celluar Signalling,2001,13(1):7-16.
[6] JANSSENS V,GODS J.Proteinphosphatase 2A:a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling[J]. Biochemical J,2001,353(3):417-439.
[7] LU J, KOVACH J S, JOHNSON F, et al. Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms[J]. Proc Natl Acad Sci USA, 2009, 106(28):11697-11702.
[8] MARTINIOVA L, LU J, CHIANG J, et al. Pharmacologic modulation of serine/threonine phosphorylation highly sensitizes PHEO in a MPC cell and mouse model to conventional chemotherapy[J]. PLoS One, 2011, 6(2):e14678.
[9] LI W, CHEN Z, GONG F R, et al. Growth of the pancreatic cancer cell line PANC-1 is inhibited by protein phosphatase 2A inhibitors through over activation of the c-Jun N-terminal kinase pathway[J]. Eur J Cancer, 2011, 47(17):2654-2664.
[10] DENG L, DONG J, WANG W. Exploiting protein phosphatase inhibitors based on cantharidin analogues for cancer drug discovery[J]. Mini Rev Med Chem, 2013, 13(8):1166-1176.
[11] HOFSTETTER C P, BURKHARDT J K, SHIN B J, et al. Protein phosphatase 2A mediates dormancy of glioblastoma multiforme-derived tumor stem-like cells during hypoxia[J]. PloS One, 2012, 7(1):e30059.
[12] WANG Q, GAO F, WANG T, et al. A nonhomologous end-joining pathway is required for protein phosphatase 2A promotion of DNA double-strand break repair[J]. Neoplasia, 2009, 11(10):1012-1021.
[13] YAN Y, CAO P T, GREER P M, et al. Protein phosphatase 2A hasan essential role in the activation of gamma-irradiationinduced G2/M checkpoint response[J]. Oncogene, 2010, 29(30):4317-4329.
[14] MI J, BOLESTA E, BRAUTIGAN D L, et al. PP2A regulates ionizing radiation-induced apoptosis through Ser46 phosphorylation of p53[J]. Molecular Cancer Therapeutics, 2009, 8(1):135-140.
[15] ZHUANG Z, LU J, LONSER R,et al. Enhancement of cancer chemotherapy by simultaneously altering cell cycle progression and DNA-damage defenses through global modification of the serine/threonine phospho-proteome[J]. Cell Cycle, 2009, 8(20):3303-3306.
[16] MCCLUSKEY A, SIM A T R, SAKOFF J A. Serine-threonine protein phosphatase inhibitors: development of potential therapeutic strategies[J]. J Med Chem, 2002, 45(6):1151-1175.
[17] HART M E, CHAMBERLIN A R, WALKOM C, et al. A modified norcantharidins: synthesis, protein phosphatases 1 and 2A inhibition, and anti-cancer activity[J]. Bioorg Med Chem Lett, 2004,14(1):1969-1973.
[18] BONNESS K, ARAGON I V, RUTLAND B, et al. Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2A[J]. Mol Cancer Ther, 2006,5(11):2727-2736.
[19] SHI Y G. Assembly and structure of protein phosphatase 2A[J]. Sci China C(Life Sci), 2009, 52(2):135-146.
[20] CASTEDO M, PERFETTINI J L, ROUMIER T, et al. Cell death by mitotic catastrophe: a molecular definition[J]. Oncogene, 2004, 23(16):2825-2837.
[21] SINCLAIR W K,MORTON R A. X-ray and ultraviolet sensitivity of synchronized Chinese hamster cells at various stages of the cell cycle[J].Biophys J,1965,5(1):1-25.
[22] XIA S X. Radiobiology(放射生物学)[M]. Beijing:Military Medical Science Press,1998:12-15.
[23] SHENG Y,MI F X.Oncology Radiobiology (肿瘤放射生物学)[M]. Beijing:China Medical Science Press, 2001:155-158.
[24] XIE B F, HAO D L, LIU Z C, et al. The effects of tea polyphenol on DNA cleavage and cell cycle of human NPC cell line CNE2 cell [J]. Chin Pharm Bull(中国药理学通报), 1999,14(15):424-427.
[25] WEI D, PARSEIS L A, KAMAK D, et al. Inhibition of protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C/CDK1 and homologous recombination repair[J]. Clin Cancer Res, 2013, 19(16):4422-4432.
[26] CHEN L, LIU L, YIN J, et al. Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway[J]. Int J Biochem Cell Biol, 2009, 41(6):1284-1295.
[27] LI H H, CAI X, SHOUSE G P, et al. A specific PP2A regulatory subunit, B56 gamma, mediates DNA damage-induced dephosphorylationof p53 at Thr55[J]. EMBO J,2007, 26(2): 402-411.
[28] MI J, BOLESTA E, BRAUTIGAN D L, et al. PP2A regulates ionizing radiation-induced apoptosis through Ser46 phosphorylation of p53[J]. Mol Cancer Ther,2009, 8(1):135-140.
[29] HANG C E, TIAN Q, WEI W,et al. Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus[J]. Neurobiol Aging, 2008, 29(11):1654-1665.
[30] CHEN C L, LIN C F, CHIANG C W, et al. Lithium inhibits ceramide-and etoposide-induced protein phosphatase 2A methylation,Bcl-2 dephosphorylation, caspase-2 activation, and apoptosis[J]. Mol Pharmacol, 2006, 70(2): 510-517.
[31] PRICE W A, STOBBE C C, PARK S J,et al. Radiosensitization of tumour cells by cantharidin and some analogues[J]. Int J Radiation Biol, 2004, 80(4): 269-279.
[32] LANKOFF A, BIALCZYK J, DZIGA D, et al. The repair of gamma-radiation-induced DNA damage is inhibited by microcystin-LR, the PP1 and PP2A phosphatase inhibitor[J]. Mutagenes, 2006, 21(1):83-90.

基金

国家自然科学基金青年科学基金资助项目(81502389)
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