TIPE3上调P-gp表达降低乳腺癌细胞对阿霉素的敏感性

doi:10.6040/j.issn.1671-7554.0.2017.210

摘要/Abstract

摘要： 目的探讨新的促癌分子肿瘤坏死因子-α诱导蛋白8样蛋白3(TIPE3)是否影响乳腺癌细胞MCF-7对阿霉素的敏感性及其机制。方法以0、0.5、1.0、1.5 μg/mL阿霉素作用于TIPE3表达质粒转染的MCF-7细胞,分别采用细胞活性检测试剂盒(CCK-8)、流式细胞术分析TIPE3对阿霉素作用的MCF-7细胞相对活性及细胞周期分布的影响;采用Annexin V/PI染色流式细胞术检测分析TIPE3对阿霉素作用的MCF-7细胞凋亡的影响;采用实时荧光定量PCR(qRT-PCR)法和蛋白印记(Western blotting)法检测核因子-kappa B(NF-κB)信号通路活化情况、多药耐药基因1(MDR 1)及多药耐药蛋白P-糖蛋白(P-gp)的表达。结果过表达TIPE3增加了阿霉素处理MCF-7细胞的相对存活率和G2/M期细胞数,降低细胞凋亡率;NF-κB信号通路活化水平增加,多药耐药基因MDR1及其表达蛋白P-gp的表达水平升高。结论 TIPE3通过活化NF-κB信号通路上调P-gp的表达进而降低MCF-7细胞对阿霉素的敏感性。

关键词: 乳腺癌, P-糖蛋白, 肿瘤坏死因子-α诱导蛋白8样蛋白3, 核因子-kappa B, 阿霉素

Abstract: Objective To investigate the mechanisms of tumor necrosis factor-α induced protein 8 like 3(TIPE3), a recently investigated oncogenic transfer protein, on modulating breast cancer cell MCF-7 sensitivity to adriamycin. Methods TIPE3-overexpressed MCF-7 cells were treated with 0, 0.5, 1.0, 1.5 μg/mL adriamycin. After that, the relative viability and cell cycle of MCF-7 cells were detected with CCK-8 method and flow cytometry; the apoptosis of MCF-7 cells was assessed with Annexin V/PI; expression of MDR 1/P-gp and activation of NF-κB signal pathway were detected with qRT-PCR and Western blotting. Results Overexpressed TIPE3 promoted MCF-7 cell proliferation, increased the number of G2/M cells and inhibited apoptosis. Furthermore, overexpressed TIPE3 protein upregulated the activation of NF-κB signal pathway and the expression of MDR1/P-gp. Conclusion TIPE3 decreased MCF-7 cells sensitivity to adriamycin by upregulating the expression of P-gp via NF-κB pathway.

Key words: Nuclear factor-kappa B, Adriamycin, Tumor necrosis factor-α induced protein 8 like 3, Breast cancer, P-gp

中图分类号:

R392.11

廉开礼,李炎,张娜,靳桂媛,刘素侠. TIPE3上调P-gp表达降低乳腺癌细胞对阿霉素的敏感性[J]. 山东大学学报（医学版）, 2017, 55(5): 36-42.

LIAN Kaili, LI Yan, ZHANG Na, JIN Guiyuan, LIU Suxia. TIPE3 decreases breast cancer cell sensitivity to adriamycin by upregulating P-gp protein expression[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(5): 36-42.

参考文献

[1] 罗年安, 屈亚琦, 董瑞. 乳腺癌的治疗进展[J]. 现代生物医学进展, 2015, 15(1): 162-166. LUO Nianan, QU Yaqi, DONG Rui. The treatment progress of the breast cancer[J]. Progress in Modern Biomedicine, 2015, 15(1): 162-166.
[2] Fan L, Strasser-Weippl K, Li JJ, et al. Breast cancer in China[J]. Lancet Oncol, 2014, 15(7): 279-289.
[3] Lei H, Wang X, Wu C. Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations[J]. J Mol Graph Model, 2012, 38(9): 279-289.
[4] Meszaros P, Klappe K, Hummel I, et al. Function of MRP1/ABCC1 is not dependent on cholesterol or cholesterol-stabilized lipid rafts[J]. Biochem J, 2011, 437(3): 483-491.
[5] 韩嘉华,朱斯琦,谢燕. 黄酮类化合物抵抗P-糖蛋白介导肿瘤多药耐药特性机制研究进展[J]. 国际药学研究杂志, 2016, 43(5): 818-823. HAN Jihua, ZHU Siqi, XIE Yan. Mechanism of flavonoids against P-glycoprotein mediated tumor multidrug resistance: Research advances[J]. J Int Pharm Res, 2016, 43(5): 818-823.
[6] 马园园, 颜天华, 程涛, 等. P-糖蛋白在细胞膜的定位和功能研究进展[J]. 西北药学杂志, 2014, 29(4): 439-442. MA Yuanyuan, YAN Tianhua, CHENG Tao, et al. Research progress on the location and function of P-glycoprotein in cell membrane[J]. Northwest Pharmaceutical Journal, 2014, 29(4): 439-442.
[7] 孙晓冉, 孙剑经, 张林西. 姜黄素逆转肿瘤多药耐药机制的研究进展[J]. 中国肿瘤, 2016, 25(4): 272-277. SUN Xiaoran, SUN Jianjing, ZHANG Linxi, et al. Research progress in curcumin reversal of multidrug resistance in tumor[J]. China Cancer, 2016, 25(4): 272-277.
[8] Deng L, Lin-Lee YC, Claret FX, et al. 2-acetylaminofluorene up-regulates rat mdrlb expression through generating reactive oxygen species that activate NF-kappaB pathway[J]. J Biol Chem, 2001, 276(1): 413-420.
[9] Kumar D, Gokhale P, Broustas C, et al. Expression of SCC-S2, an antiapoptotic molecule, correlates with enhanced proliferation and tumorigenicity of MDA-MB-435 cells[J]. Oncogene, 2004, 23(2): 612-616.
[10] Sun H, Gong S, Carmody RJ, et al. TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis[J]. Cell, 2008, 133(3): 415-426.
[11] Kumar D, Whiteside TL, Kasid U. Identification of a novel tumor necrosis factor-alpha-inducible gene, SCC-S2, containing the consensus sequence of a death effector domain of fas-associated death domain-like interleukin- 1beta-converting enzyme-inhibitory protein[J]. J Biol Chem, 2000, 275(4): 2973-2978.
[12] Porturas TP, Sun H, Buchlis G, et al. Crucial roles of TNFAIP8 protein in regulating apoptosis and Listeria infection[J]. J Immunol, 2015, 194(12): 5743-5750.
[13] Hitomi J, Christofferson DE, Ng A, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway[J]. Cell, 2008, 135(7): 1311-1323.
[14] Gus-Brautbar Y, Johnson D, Zhang L, et al. The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras[J]. Molecular cell, 2012, 45(5): 610-618.
[15] Fayngerts SA, Wu J, Oxley CL, et al. TIPE3 is the transfer protein of lipid second messengers that promote cancer[J]. Cancer cell, 2014, 26(4): 465-478.
[16] Cui J, Hao C, Zhang W, et al. Identical expression profiling of human and murine TIPE3 protein reveals links to its functions[J]. J Histochem Cytochem, 2015, 63(3): 206-216.
[17] Shaw JA, Stebbing J. Circulating free DNA in the management of breast cancer[J]. Ann Transl Med, 2014, 2(1): 3.
[18] Ohta T. Breast cancer[J]. Nihon Rinsho, 2010, 68(Suppl 8): 438-443.
[19] 周志兵,魏文嵩,杨世昕,等. 紫杉醇联合表阿霉素、环磷酰胺治疗乳腺癌的近期疗效及安全性分析[J]. 医学理论与实践, 2017, 30(4): 550-551.
[20] 刘晓, 邵方元, 陈宏远. 阿霉素抗肿瘤分子机制的研究进展[J].中国医药生物技术, 2012, 7(5): 373-375.
[21] Li QQ, Wang WJ, Xu JD, et al. Involvement of CD147 in regulation of multidrug resistance to P-gp substrate drugs and in vitro invasion in breast cancer cells[J]. Cancer Sci, 2007, 98(7): 1064-1069.
[22] Xu JW, Li QQ, Tao LL, et al. Involvement of EGFR in the promotion of malignant properties in multidrug resistant breast cancer cells[J]. Int J Oncol, 2011, 39(6): 1501-1509.
[23] Amiri-Kordestani L, Basseville A, Kurdziel K, et al. Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies[J]. Drug Resist Updat, 2012, 15(1-2): 50-61.
[24] Kuo MT, Liu Z, Wei Y, et al. Inductio of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-kB signaling[J]. Oncogene, 2002, 21(13): 1945-1954.
[25] Osborn MT, Berry A, Ruberu MS, et al. Phorbol ester induced MDR1 expression in K562 cells occurs independently of mitogen-activated protein kinase signaling pathways[J]. Oncogene, 1999, 18(42): 5756-5764;
[26] Morgan TM, Koreckij TD, Corey E, et al. Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway[J]. Curr Cancer Drug Targets, 2009, 9(2): 237-249.
[27] Zhang BG, Hu L, Zang MD, et al. Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development[J]. Oncotarget, 2016, 7(9): 9788-9800.
[28] Kaili Lian, Chao Ma, Chunyan Hao, et al. TIPE3 protein promotes breast cancer metastasis through activating AKT and NF-κB signaling pathways[J]. Oncotarget, 2017, 23. doi: 10.18632/oncotarget.16522.

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