Lycorine上调p53非依赖的p21转录机制的研究
摘要
白血病是严重危害人类健康的造血组织恶性疾病,目前化学治疗仍是白血病治疗的主要途径。Lycorine(石蒜碱)是从我国广泛分布的多年生草本植物石蒜鳞茎中分离出的一种单体化合物,属于异喹啉类(isoquinoline)生物碱,具有广谱的抗白血病作用。本研究以人急性早幼粒白血病细胞株HL-60和人慢性粒细胞白血病细胞株K562作为实验对象,研究lycorine在白血病细胞中上调p53非依赖的p21转录过程中相关蛋白表达的变化,以及lycorine对p21转录的靶向特异性,进一步阐明lycorine对白血病p53非依赖的p21转录的分子机制。
本课题用不同浓度的lycorine作用HL-60细胞和K562细胞24h后,提取总蛋白,通过Western blotting检测lycorine作用后p53蛋白的表达变化及调控p21转录相关蛋白：E2F、Rb、c-myc、HDAC1、HDAC3的表达变化。结果发现,在p53野生型的K562细胞中,lycorine上调p21的表达不是通过上调p53来实现的,表明lycorine对p21的调控是p53非依赖的；随着lycorine药物作用浓度的逐渐增大,HL-60细胞和K562细胞中E2F和Rb蛋白表达量上调,c-myc蛋白表达量下调,而HDAC1和HDAC3蛋白表达量没有明显差异,表明Rb/E2F途径及c-myc途径参与了p21的转录调控,HDACs途径不参与p21的转录调控。另外,为检测p21靶标的特异性,以p21 Si RNA封闭p21基因的表达后,用2.5μM lycorine药物干预p21封闭前后的细胞,采用流式细胞术检测p21封闭后的细胞凋亡变化。结果发现,p21 siRNA+lycorine组细胞凋亡百分率较阴性序列+lycorine组有明显减少。
综上所述,lycorine能够通过上调E2F,下调c-myc的表达来调控p53非依赖的p21的转录；阐明了p21是lycorine抗白血病的关键效应分子。
Leukemia is a hematological malignancy, which is one of the greatest health challenges facing the world today. Chemotherapy is still considered one of the most effective methods or the basis of other treatments. Previous studies in our group had found lycorine activated p21 transcription in a p53-independent mechanism after treatment in leukemia. To further elucidate anti-leukemia action of lycorine, this research focused on the expression change of proteins associated with p21 transcription in p53-independent pathway in HL-60 and K562 cells and specificity of p21 transcription after treatment of lycorine
After HL-60 and K562 cells were treated with different concentrations of lycorine for 24h, Western blotting was used to identify the effect of lycorine on the expression of E2F、Rb、c-myc、HDAC1 and HDAC3. The results showed that expression of E2F and Rb were up-regulated, c-myc was down-regulated in HL-60 and K562 cells. But the expression of HDAC1 and HDAC3 was no changed in HL-60 and K562 cells. Furthermore, RNAi was performed to interfere the expression of p21 gene, then flow cytometry was used to detect the cell apotosis rate after treated by 2.5μM lycorine. Compared to the scrambled sequence+lycorine group, the apoptosis rate in p21 siRNA+lycorine group was significantly decreased. This result suggested that lycocrine was specificly targeted to p21.
本课题用不同浓度的lycorine作用HL-60细胞和K562细胞24h后,提取总蛋白,通过Western blotting检测lycorine作用后p53蛋白的表达变化及调控p21转录相关蛋白：E2F、Rb、c-myc、HDAC1、HDAC3的表达变化。结果发现,在p53野生型的K562细胞中,lycorine上调p21的表达不是通过上调p53来实现的,表明lycorine对p21的调控是p53非依赖的；随着lycorine药物作用浓度的逐渐增大,HL-60细胞和K562细胞中E2F和Rb蛋白表达量上调,c-myc蛋白表达量下调,而HDAC1和HDAC3蛋白表达量没有明显差异,表明Rb/E2F途径及c-myc途径参与了p21的转录调控,HDACs途径不参与p21的转录调控。另外,为检测p21靶标的特异性,以p21 Si RNA封闭p21基因的表达后,用2.5μM lycorine药物干预p21封闭前后的细胞,采用流式细胞术检测p21封闭后的细胞凋亡变化。结果发现,p21 siRNA+lycorine组细胞凋亡百分率较阴性序列+lycorine组有明显减少。
综上所述,lycorine能够通过上调E2F,下调c-myc的表达来调控p53非依赖的p21的转录；阐明了p21是lycorine抗白血病的关键效应分子。
Leukemia is a hematological malignancy, which is one of the greatest health challenges facing the world today. Chemotherapy is still considered one of the most effective methods or the basis of other treatments. Previous studies in our group had found lycorine activated p21 transcription in a p53-independent mechanism after treatment in leukemia. To further elucidate anti-leukemia action of lycorine, this research focused on the expression change of proteins associated with p21 transcription in p53-independent pathway in HL-60 and K562 cells and specificity of p21 transcription after treatment of lycorine
After HL-60 and K562 cells were treated with different concentrations of lycorine for 24h, Western blotting was used to identify the effect of lycorine on the expression of E2F、Rb、c-myc、HDAC1 and HDAC3. The results showed that expression of E2F and Rb were up-regulated, c-myc was down-regulated in HL-60 and K562 cells. But the expression of HDAC1 and HDAC3 was no changed in HL-60 and K562 cells. Furthermore, RNAi was performed to interfere the expression of p21 gene, then flow cytometry was used to detect the cell apotosis rate after treated by 2.5μM lycorine. Compared to the scrambled sequence+lycorine group, the apoptosis rate in p21 siRNA+lycorine group was significantly decreased. This result suggested that lycocrine was specificly targeted to p21.
引文
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[3]王艾丽.血液病社会行为危险因素研究：[硕士学位论文].苏州：苏州大学,2006
[4]曹晖.白血病的发病及治疗进展.实用医技杂志,2007,16(14)：2253-2254
[5]Wang X, Wong SC, Pan J, et al. Evidence of cisplatin-induced senescent-like growth arrest in nasopharyngeal carcinoma cells. Cancer Res,1998,58(22):5019-5022
[6]阮龙喜.石蒜碱植物生物碱的一些研究进展.药学通报,1988,23(8)：453
[7]Liu J,Hu WX,He LF,et al. Effects of lycorine on HL-60 cell via arresting cell cycle and inducing apoptosis. FEBS Lerrers,2004,578(3):245-250
[8]Liu J,Li Y,Tang LJ,et al. Treatment of lycorine on SCID mice model with human APL cells. Biomedicine & Pharmacotherapy,2007,61(4):229-234
[9]Li Y,Liu J,Tang LJ,et al. Lycorine induces apoptosis and G0/G1 cell cycle arrest of the human multiple myeloma KM3 cell line. Oncology reports,2007,17(4):377-348
[10]Falus A. Cytokine receptor architecture, structure and genetic assembly. Immunol Lett,1995,44(2-3):221-223
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[12]Liu J, Hu JL, Shi BW, et al. Up-regulation of p21 and TNF-a is mediated in lycorine-induced death of HL-60 cells. Cancer Cell International,2010,10:25-33
[13]Wetzler M, Dodge RK, Mroze Kk,et al. Prospective karyotype analysis in adult acute lymphoblastic leukemia:The cancer and leukemia group B exprerience. Blood,1999, 93(11):3983-3993
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[25]Sowa Y, Orita T, Minamikawa-Hiranabe S, et al. Sp3, but not Spl, mediates the transcriptional activation of the p21/WAFl/Cipl gene promoter by histone deacetylase inhibitor. Cancer Res,1999,59(17):4266-4270.
[26]Gui CY, Ngo L, Xu WS, et al. Histone deacetylase (HDAC) inhibitor activation of p21WAFl involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A.,2004,101(5):1241-1246.
[27]Petrella A, D'Acunto CW, Rodriquez M, et al. Effects of FR235222, a novel HDAC inhibitor, in proliferation and apoptosis of human leukaemia cell lines:role of annexin Al. Eur J Cancer,2008,44(5):740-749.
[28]Bi G, Jiang G. The molecular mechanism of HDAC inhibitors in anticancer effects. Cell Mol Immunol,2006,3(4):285-290.
[29]Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov,2006,5(9):769-784
[30]Ccoqueret O. New roles for p21 and p27 cell-cycle inhibitors:a function for each cell compartment? Trends Cell Biol.2003,13(2):65-70
[31]Seville LL,Shah N,Westwell AD,et al. Modulation of pRB/E2F functions in the regulation of cell cycle and in cancer. Curr Cancer Drug Targets,2005,5(3):159-170
[32]Tomicic MT,Thust R,Kaina B. Gancicilovir-induced apoptosis in HSV-lthymidine kinase expressing cells:critical role of DNA breaks, Bcl-2 decline and caspase-9 activation. Oncogene,2002,21(14):2141-2153
[33]Ookawa K, Tsuchida S, Kohno T, et al. Alterations in expression of E2F-1 and E2F-responsive genes by RB,p53 and p21Sdil/WAFl/Cipl expression. FEBS Lett, 2001,500(1-2):25-30
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[39]Sauve S, Tremblay L, Lavigne P. The NMR solution structure of amutant of the Max b/HLH/LZ free of DNA:insights into the specific and reversible DNA binding mechanism of dimeric transcription factor. J Mol Biol,2004,342(3):813-832
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[42]Ocker M, Schneider-Stock R. Histone deacetylase inhibitors:signalling towards p21cipl/wafl. Int J Biochem Cell Biol,2007,39(7-8):1367-1374
[43]Roberts CW,Orkin SH. The SWI/SNF complex-chromatin and cancer. Nat Rev Cancer,2004,4(2):133-142.
[1]Hasselgren PO et al. Muscle cachexia:current concepts of intracellular mechanisms and molecular regulation. Ann Surg,2001,233:9-17
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[2]张海苗,张静平,彭芳等.急性白血病化疗患者焦虑、抑郁状况及其生命质量的关系Chinese General Practice,2010,13 (12A):3906-3908
[3]王艾丽.血液病社会行为危险因素研究：[硕士学位论文].苏州：苏州大学,2006
[4]曹晖.白血病的发病及治疗进展.实用医技杂志,2007,16(14)：2253-2254
[5]Wang X, Wong SC, Pan J, et al. Evidence of cisplatin-induced senescent-like growth arrest in nasopharyngeal carcinoma cells. Cancer Res,1998,58(22):5019-5022
[6]阮龙喜.石蒜碱植物生物碱的一些研究进展.药学通报,1988,23(8)：453
[7]Liu J,Hu WX,He LF,et al. Effects of lycorine on HL-60 cell via arresting cell cycle and inducing apoptosis. FEBS Lerrers,2004,578(3):245-250
[8]Liu J,Li Y,Tang LJ,et al. Treatment of lycorine on SCID mice model with human APL cells. Biomedicine & Pharmacotherapy,2007,61(4):229-234
[9]Li Y,Liu J,Tang LJ,et al. Lycorine induces apoptosis and G0/G1 cell cycle arrest of the human multiple myeloma KM3 cell line. Oncology reports,2007,17(4):377-348
[10]Falus A. Cytokine receptor architecture, structure and genetic assembly. Immunol Lett,1995,44(2-3):221-223
[11]Cheng L, Zhou XJ. Review on anticancer mechanism of same plant alkaloids. Chinese Traditional and Herbal Drugs,2004,35(2):825-828
[12]Liu J, Hu JL, Shi BW, et al. Up-regulation of p21 and TNF-a is mediated in lycorine-induced death of HL-60 cells. Cancer Cell International,2010,10:25-33
[13]Wetzler M, Dodge RK, Mroze Kk,et al. Prospective karyotype analysis in adult acute lymphoblastic leukemia:The cancer and leukemia group B exprerience. Blood,1999, 93(11):3983-3993
[14]Gartel AL, Tyner AL. The Role of the Cyclin-dependent Kinase Inhibitor p21 in Apoptosis. Molecular Cancer Therapeutics,2002,1(8):639-649
[15]el-Deiry WS, Harper JW, O'Connor PM, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res,1994,54(5):1169-1174
[16]Wolf D, Rotter V. Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells. Proc Natl Acad Sci USA,1985, 82(3):790-794.
[17]Weinberg RA:The Retinoblastoma Protein and Cell-Cycle Control. Cell,1995, 81(3):323-330
[18]Gartel AL, Najmabadi F, Goufman E, et al. A role for E2F1 in Ras activation of p21(wafl/cipl) transcription. Oncogene,2000,19(7):961-964.
[19]Glozak MA, Sengupta N, Zhang X, et al. Acetylation and deacetylation of non-histone proteins. Gene,2005,363:15-23.
[20]Gaubatz S, Lindeman GJ, Ishida S, et al. E2F4 and E2F5 play an essential role in pocket protein-mediated Gl control. Mel Cell,2000,6(3):729-735
[21]Gartel AL, Shchors K. Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes. Exp Cell Res,2003,283(1):17-21.
[22]Wu S, Cetinkaya C, Munoz-Alonso MJ, et al. Myc represses differentiation-induced p21CIPl expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene,2003,22(3):351-360
[23]Ammanamanchi S, Freeman JW, Brattain MG. Acetylated Sp3 is a transcriptional activator. J Biol Chem,2003,278(37):35775-35780.
[24]Gartel AL, Radhakrishnan SK. Lost in transcription:p21 repression, mechanisms, and consequences. Cancer Res,2005,65(10):3980-3985.
[25]Sowa Y, Orita T, Minamikawa-Hiranabe S, et al. Sp3, but not Spl, mediates the transcriptional activation of the p21/WAFl/Cipl gene promoter by histone deacetylase inhibitor. Cancer Res,1999,59(17):4266-4270.
[26]Gui CY, Ngo L, Xu WS, et al. Histone deacetylase (HDAC) inhibitor activation of p21WAFl involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A.,2004,101(5):1241-1246.
[27]Petrella A, D'Acunto CW, Rodriquez M, et al. Effects of FR235222, a novel HDAC inhibitor, in proliferation and apoptosis of human leukaemia cell lines:role of annexin Al. Eur J Cancer,2008,44(5):740-749.
[28]Bi G, Jiang G. The molecular mechanism of HDAC inhibitors in anticancer effects. Cell Mol Immunol,2006,3(4):285-290.
[29]Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov,2006,5(9):769-784
[30]Ccoqueret O. New roles for p21 and p27 cell-cycle inhibitors:a function for each cell compartment? Trends Cell Biol.2003,13(2):65-70
[31]Seville LL,Shah N,Westwell AD,et al. Modulation of pRB/E2F functions in the regulation of cell cycle and in cancer. Curr Cancer Drug Targets,2005,5(3):159-170
[32]Tomicic MT,Thust R,Kaina B. Gancicilovir-induced apoptosis in HSV-lthymidine kinase expressing cells:critical role of DNA breaks, Bcl-2 decline and caspase-9 activation. Oncogene,2002,21(14):2141-2153
[33]Ookawa K, Tsuchida S, Kohno T, et al. Alterations in expression of E2F-1 and E2F-responsive genes by RB,p53 and p21Sdil/WAFl/Cipl expression. FEBS Lett, 2001,500(1-2):25-30
[34]Ahlander J, Bosco G, The RB/E2F pathway and regulation of RNA processing. Biochem and Biophys Res Commun,2009,384(3):280-283
[35]Zhang HS, Gavin M, DahiyaA, et al. Exit from Gl and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell,2000,101(1):79-89.
[36]Ma Y, Croxton R, Moorer Jr RL, et al. Identification of novel E2F1-regulated genes by microarray, Arch Biochem Biophys,2002,399(2):212-224.
[37]Dang CV, O'Donnell KA, Zeller KI, et al. The c-Myc target gene network. Semin Cancer Biol.2006,16(4):253-264.
[38]Zeller KI, Jegga AG, Aronow BJ, et al. An integrated database of genes responsive to the Myc oncogenic transcription factor:identification of direct genomic targets. Genome Biol,2003,4(10):R69
[39]Sauve S, Tremblay L, Lavigne P. The NMR solution structure of amutant of the Max b/HLH/LZ free of DNA:insights into the specific and reversible DNA binding mechanism of dimeric transcription factor. J Mol Biol,2004,342(3):813-832
[40]Zhu H, Liu S, Zhou C, et al. Anti-apoptsis gene survivin promotes cell growth and transformation. Zhonghua Yi Xue Za Zhi,2002,82(5):338-340
[41]Song Y, Kong BH, Liu PS, et al. Relationship between human telomerase reverse transcriptase transcriptional level and telomerase activity in three ovarian cancer cellines[J]. Ai Zheng,2003,22(5):486-491.
[42]Ocker M, Schneider-Stock R. Histone deacetylase inhibitors:signalling towards p21cipl/wafl. Int J Biochem Cell Biol,2007,39(7-8):1367-1374
[43]Roberts CW,Orkin SH. The SWI/SNF complex-chromatin and cancer. Nat Rev Cancer,2004,4(2):133-142.
[1]Hasselgren PO et al. Muscle cachexia:current concepts of intracellular mechanisms and molecular regulation. Ann Surg,2001,233:9-17
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