丹参酮ⅡA诱导肾细胞癌细胞凋亡及其分子机制
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摘要
【研究背景】
肾细胞癌（renal cell carcinoma，RCC）是最为普遍肾实质肿瘤，其具有高致死率，并且发生率也持续升高。目前，临床治疗肾细胞癌主要采取手术治疗、免疫治疗以及疫苗治疗等方法，然而肾细胞癌病人的预后仍然较差；因此，新药物及其机制研发仍十分迫切。传统中药由于具有低毒，特异性等特征，在肿瘤的治疗方面备受关注。丹参酮ⅡA为传统中草药丹参（Salvia miltiorrhiza BUNGE）根部中提取物，传统药理公认其具有抗氧化以及抗衰老功效。近来研究表明：丹参酮ⅡA能够发挥抗肿瘤活性，成为研究热点。然而，关于丹参酮ⅡA是否对肾细胞癌有抗肿瘤作用效果其分子机制如何尚待明确。
【研究目的】
研究丹参酮ⅡA诱导肾细胞癌786-O细胞凋亡及其分子机制。具体来说，明确丹参酮ⅡA处理786-O细胞后，对786-O细胞生长活力的影响；探讨丹参酮ⅡA诱导786-O细胞周期阻滞和细胞凋亡的信号通路及其分子机制。
【研究方法】
首先，采用不同浓度的丹参酮ⅡA（0μg/mL，1μg/mL，2μg/mL，4μg/mL，8μg/mL）处理24h的肾细胞癌786-O细胞后，用MTT方法检测786-O细胞活力的影响。同时，采用不同浓度的丹参酮ⅡA（0μg/mL，1μg/mL，2μg/mL，4μg/mL，8μg/mL，10μg/mL，20μg/mL，30μg/mL和40μg/mL）处理24h的正常肾细胞293A细胞后，同样应用MTT方法检测丹参酮ⅡA处理24h的293A细胞活力。随后，应用流式细胞技术（PI单染色）分析不同浓度丹参酮ⅡA处理前后786-O细胞周期分布变化，以明确丹参酮ⅡA对786-O细胞生长影响。再采用western blot检测细胞周期阻滞相关靶蛋白cyclin A的表达水平，来印证786-O细胞的周期阻滞。为进一步探讨周期阻滞的分子机制，用western blot检测p21和p53的表达水平。然后，用流式细胞术（AnnexinV-FITC/PI双染色）检测丹参酮ⅡA处理786-O细胞后，细胞凋亡的情况。并用western blot检测p53下游靶基因（Fas和bax）和凋亡效应蛋白caspase-3表达水平。最后，采用western blot实验检测MDM2的表达，以确定MDM2是否影响了p53的上调。还通过构建GFP-NPM质粒，以GFP-NPM转染786-O细胞后，应用激光共聚焦显微镜观察GFP-NPM细胞定位情况；并且用免疫共沉淀技术验证53与NPM是否发生物理相互作用，来确定p53是否受NPM正向调控。
【研究结果】
（1） MTT实验表明丹参酮ⅡA处理24小时对786-O细胞的半数抑制浓度IC50约为2μg/mL；而丹参酮ⅡA处理24小时对人胚肾293A细胞的半数抑制浓度IC50约为8μg/mL。
（2）应用浓度分别为0，2，4和8μg/mL的丹参酮ⅡA处理肾细胞癌786-O细胞24小时后，流式细胞术PI单染色法检测出细胞周期处于S期的细胞所占百分比分别为10.0%，11.5%，20.4%和23.3%。western blot表明细胞周期S期的标志性蛋白cyclin A表达呈药物浓度梯度提高。丹参酮ⅡA处理引起p21蛋白表达显著升高，并呈药物浓度依赖方式上调。p53蛋白表达显著升高，并且呈现药物浓度依赖关系。
（3）流式细胞术AnnexinV-FITC/PI染色检测细胞凋亡的结果表明，当用不同浓度丹参酮ⅡA（2，4和8μg/mL）处理肾细胞癌786-O细胞24小时后，早期凋亡细胞数量从8.6％（对照组）分别增加到27.2％，27.8％和28.8%；晚期凋亡细胞从对照组的2.9％分别增加到9.2％，12.5％和13.9%。凋亡细胞百分率则从对照组的11.5%分别增加到36.4％，40.3％和42.7%，作用效果与丹参酮ⅡA药物浓度呈正比。western blot显示丹参酮ⅡA处理Fas表达没有变化，且丹参酮ⅡA处理引起bax蛋白表达显著升高，呈现药物浓度依赖关系。还显示了caspase-3表达升高，表明caspase-3被激活。
（4） western blot结果显示p53负性调节子MDM2表达水平没有变化。激光共聚焦显微镜观察到GFP-NPM从核仁移位到核浆中。免疫共沉淀实验表明NPM能和p53发生相互作用。
【结论】
（1）丹参酮ⅡA能够以浓度依赖方式显著抑制786-O细胞生长活力；丹参酮ⅡA对肾细胞癌786-O细胞有显著的抑制作用，但对正常的人胚肾293A细胞没有明显的细胞毒性作用。
（2）丹参酮ⅡA可诱导肾细胞癌786-O细胞周期S期阻滞。其分子机制为：丹参酮ⅡA诱导肾细胞癌786-O细胞p53及其转录调控靶基因p21上调，且p53通过转录上调p21蛋白表达水平，参与介导丹参酮ⅡA诱导肾细胞癌786-O细胞周期S期阻滞。
（3）丹参酮ⅡA可进一步诱导肾细胞癌786-O细胞凋亡。在此过程中，p53转录下游靶基因Fas没有变化，而bax上调，凋亡效应蛋白caspase-3上调，表明bax参与丹参酮ⅡA诱导的肾细胞癌786-O细胞凋亡，丹参酮ⅡA诱导的肾细胞癌786-O细胞凋亡是通过线粒体途径，而非循Fas通道。
（4）丹参酮ⅡA处理肾细胞癌786-O细胞，可使其核仁蛋白NPM从核仁穿梭到核浆，且NPM和p53发生相互作用，表明NPM参与p53翻译后调控，维持了p53的稳定性，从而使p21蛋白表达水平上调。
本研究不但证明了丹参酮ⅡA可有效地抑制肾细胞癌786-O细胞生长增殖，并诱导细胞发生周期阻滞以至凋亡，还通过分子实验数据揭示了丹参酮ⅡA处理肾细胞癌786-O细胞通过驱动NPM从细胞核仁穿梭到核浆，使与核浆定位的p53发生共定位，进而增强NPM和p53相互作用，促进p53稳定性，继而转录激活其下游靶基因p21和bax蛋白水平上调的抑癌作用机制。并通过对正常人胚肾293A细胞的作用研究，证明丹参酮ⅡA可在基本不影响正常细胞情况下起肿瘤抑制作用，对有关肿瘤治疗的研究可起重要指导作用。
[Background]
Renal cell carcinoma (RCC), the most common cancer arising from the renalparenchyma, causes prevalent deaths worldwide and its incidence continues to rise. Althoughseveral therapeutic approaches have been applied to the treatment of RCC, including surgery,immunological therapies and vaccine treatment, further improvements are still needed.Therefore, it is extremely necessary to explore and develop new anti-cancer drugs. Notably,Traditional Chinese Medicine (TCM) draws much attention due to its dramatic roles in cancertherapy with the characteristics of low-toxicity and specificity, etc. Tanshinone ⅡA (Tan ⅡA),one of the phytochemical compounds isolated from the Chinese medicinal herb Danshen (rootof Salvia miltiorrhiza Bunge), possesses antioxidant and anti-aging properties. At present, TanⅡA has become a research hotspot, because it’s anti-cancer activity. However, the effect ofTan ⅡA on human RCC and its molecular mechanism need to be clarified.
[Objective]
Therefore, we aim to investigate the apoptotic effect of Tan ⅡA on human RCC786-Ocells and unveil the molecular mechanism by which it functions. Specifically, the viability of786-O cells following Tan ⅡA treatment was examined at first. Further, we delved into thesignaling pathways plus molecular mechanism by which Tan ⅡA induced786-O cell cyclearrest and apoptosis.
[Methods]
The viability of the786-O cells treated with Tan ⅡA (0μg/mL,1μg/mL,2μg/mL,4μg/mL and8μg/mL) was measured by MTT assay. As a comparison, human embryonickidney (HEK)293A cells were also treated with Tan ⅡA（0μg/mL,1μg/mL,2μg/mL,4μg/mL,8μg/mL,10μg/mL,20μg/mL,30μg/mL and40μg/mL）for24h and then subjectedto MTT assay. To demonstrate the growth inhibition of786-O cells induced by Tan ⅡA, thecell cycle distribution of786-O cells treated with and without Tan ⅡA was analyzed usingFlow cytometry (PI staining). To confirm cell cycle profile, the level of cyclin A proteinwhich is active in the S phase was subjected to western blot (WB). Moreover, to illustrate the molecular mechanism underlying cell cycle arrest, the expression levels of p21and p53whichare related with cell cycle checkpoints were determined by WB. On the other hand, TanⅡA-induced apoptosis was assessed through Flow cytometry (Annevin V/PI staining).Thereafter, the expression levels apoptosis-related molecules including Fas and bax which aretranscriptionally activated by p53and caspase-3which is an apoptotic executor wereexamined by WB. In order to reveal the molecular mechanism of p53up-regulation, the levelof MDM2protein which is a p53negative regulator was tested by WB. At last, a plasmidcontaining GFP-tagged NPM was constructed, and its sub-cellular localization was checkedby confocal microscope after its transfection in786-O cells. The physical interaction betweenNPM and p53was confirmed via co-immnunoprecipitation.
[Results]
(1) The MTT assay indicated that Tan ⅡA treatment for24h induced a marked inhibition ofthe growth of786-O cells. The half maximal inhibitory concentration (IC50) value forTan ⅡA treated786-O were estimated to be2μg/mL, whereas that for the Tan ⅡAtreated293A was8μg/mL.
(2) When786-O cells were treated with Tan ⅡA (0,2,4and8μg/ml) for24h, Flowcytometry analysis (PI stain) showed that the percentages of786-O cells in S-phasewere10.0%,11.5%,20.4%and23.3%, respectively. WB indicated that Tan ⅡA induceda dose-dependent upregulation of cyclin A. At the same time, p53and its downstreamgene p21were also increased in Tan ⅡA treated786-O cells, in a dose-dependentmanner.
(3) Following the treatment of786-O cells for24h with Tan ⅡA (2,4and8μg/mL), thenumber of early apoptotic cells increased from8.6(control) to27.2,27.8and28.8%,respectively. While the number of late apoptotic cells respectively increased from2.9(control) to9.2,12.5and13.9%. The total percentage of apoptotic cells was directlyrelated to the Tan ⅡA concentration, increased from11.5%(control) to36.4,40.3and42.7%. Tan ⅡA treatment resulted in a significant dose-dependent increase in the levelof bax and caspase-3.
(4) WB showed no change in the level of MDM2protein which is a negative regulator ofp53. Confocal microscopy showed that Tan ⅡA treatment resulted in a nucleoplasmictranslocation of GFP-tagged NPM from nucleolus. Co-immunoprecipitation tested thatthere was physical interaction between NPM and p53.
[Conclusion]
(1) Tan ⅡA treatment can cause significant dose-dependent inhibition of786-O cell growth,while Tan ⅡA treatment results in minor cytotoxicity on293A cells.
(2) Tan ⅡA treatment can induce S phase cell cycle arrest of786-O cells. The molecularmechanism can be illustrated by the upregulation of p53and its transcriptional targetgene p21, which are involved in S phase cell cycle arrest of786-O cells induced by TanⅡA treatment.
(3) Tan ⅡA treatment can further induce human RCC786-O cell apoptosis. In the apoptotic786-O cells treated with Tan ⅡA, the level of Fas proteins expression shows no change,in contrast, the expression level of bax protein increases. As a result, there is anupregulation of the apoptotic executor caspase-3. These data indicate that bax isinvolved in Tan ⅡA-induced cell apoptosis; Tan ⅡA-induced apoptosis is through amitochondrial pathway rather than Fas pathway.
(4) The translocation of Nucleolar protein NPM from nucleolus to nucleoplasm in786-Ocells after Tan ⅡA treatment and the physical interaction between NPM and p53indicates that NPM may be involved in the regulation of p53stability at apost-translational level, and ensuing upregulation of p21.
Our present study demonstrates that Tan ⅡA treatment can cause an effective growthinhibition and cell cycle arrest followed by apoptosis in human RCC786-O cells. Tan ⅡAtreatment can also trigger the translocation of NPM from nucleolus to nucleoplasm.Subsequently, Nucleoplasmic NPM can enhance p53stability via direct interaction betweenthe two, as a result, the downstream targeted genes including p21and bax are upregulated. Itis remarkable that Tan ⅡA has reduced cycotoxicity on HEK293A cells comparing with786-O cells, which suggests that Tan ⅡA has mild side effect on normal cells. Our researchwill provide promising guideline for the tumor therapy.
肾细胞癌（renal cell carcinoma，RCC）是最为普遍肾实质肿瘤，其具有高致死率，并且发生率也持续升高。目前，临床治疗肾细胞癌主要采取手术治疗、免疫治疗以及疫苗治疗等方法，然而肾细胞癌病人的预后仍然较差；因此，新药物及其机制研发仍十分迫切。传统中药由于具有低毒，特异性等特征，在肿瘤的治疗方面备受关注。丹参酮ⅡA为传统中草药丹参（Salvia miltiorrhiza BUNGE）根部中提取物，传统药理公认其具有抗氧化以及抗衰老功效。近来研究表明：丹参酮ⅡA能够发挥抗肿瘤活性，成为研究热点。然而，关于丹参酮ⅡA是否对肾细胞癌有抗肿瘤作用效果其分子机制如何尚待明确。
【研究目的】
研究丹参酮ⅡA诱导肾细胞癌786-O细胞凋亡及其分子机制。具体来说，明确丹参酮ⅡA处理786-O细胞后，对786-O细胞生长活力的影响；探讨丹参酮ⅡA诱导786-O细胞周期阻滞和细胞凋亡的信号通路及其分子机制。
【研究方法】
首先，采用不同浓度的丹参酮ⅡA（0μg/mL，1μg/mL，2μg/mL，4μg/mL，8μg/mL）处理24h的肾细胞癌786-O细胞后，用MTT方法检测786-O细胞活力的影响。同时，采用不同浓度的丹参酮ⅡA（0μg/mL，1μg/mL，2μg/mL，4μg/mL，8μg/mL，10μg/mL，20μg/mL，30μg/mL和40μg/mL）处理24h的正常肾细胞293A细胞后，同样应用MTT方法检测丹参酮ⅡA处理24h的293A细胞活力。随后，应用流式细胞技术（PI单染色）分析不同浓度丹参酮ⅡA处理前后786-O细胞周期分布变化，以明确丹参酮ⅡA对786-O细胞生长影响。再采用western blot检测细胞周期阻滞相关靶蛋白cyclin A的表达水平，来印证786-O细胞的周期阻滞。为进一步探讨周期阻滞的分子机制，用western blot检测p21和p53的表达水平。然后，用流式细胞术（AnnexinV-FITC/PI双染色）检测丹参酮ⅡA处理786-O细胞后，细胞凋亡的情况。并用western blot检测p53下游靶基因（Fas和bax）和凋亡效应蛋白caspase-3表达水平。最后，采用western blot实验检测MDM2的表达，以确定MDM2是否影响了p53的上调。还通过构建GFP-NPM质粒，以GFP-NPM转染786-O细胞后，应用激光共聚焦显微镜观察GFP-NPM细胞定位情况；并且用免疫共沉淀技术验证53与NPM是否发生物理相互作用，来确定p53是否受NPM正向调控。
【研究结果】
（1） MTT实验表明丹参酮ⅡA处理24小时对786-O细胞的半数抑制浓度IC50约为2μg/mL；而丹参酮ⅡA处理24小时对人胚肾293A细胞的半数抑制浓度IC50约为8μg/mL。
（2）应用浓度分别为0，2，4和8μg/mL的丹参酮ⅡA处理肾细胞癌786-O细胞24小时后，流式细胞术PI单染色法检测出细胞周期处于S期的细胞所占百分比分别为10.0%，11.5%，20.4%和23.3%。western blot表明细胞周期S期的标志性蛋白cyclin A表达呈药物浓度梯度提高。丹参酮ⅡA处理引起p21蛋白表达显著升高，并呈药物浓度依赖方式上调。p53蛋白表达显著升高，并且呈现药物浓度依赖关系。
（3）流式细胞术AnnexinV-FITC/PI染色检测细胞凋亡的结果表明，当用不同浓度丹参酮ⅡA（2，4和8μg/mL）处理肾细胞癌786-O细胞24小时后，早期凋亡细胞数量从8.6％（对照组）分别增加到27.2％，27.8％和28.8%；晚期凋亡细胞从对照组的2.9％分别增加到9.2％，12.5％和13.9%。凋亡细胞百分率则从对照组的11.5%分别增加到36.4％，40.3％和42.7%，作用效果与丹参酮ⅡA药物浓度呈正比。western blot显示丹参酮ⅡA处理Fas表达没有变化，且丹参酮ⅡA处理引起bax蛋白表达显著升高，呈现药物浓度依赖关系。还显示了caspase-3表达升高，表明caspase-3被激活。
（4） western blot结果显示p53负性调节子MDM2表达水平没有变化。激光共聚焦显微镜观察到GFP-NPM从核仁移位到核浆中。免疫共沉淀实验表明NPM能和p53发生相互作用。
【结论】
（1）丹参酮ⅡA能够以浓度依赖方式显著抑制786-O细胞生长活力；丹参酮ⅡA对肾细胞癌786-O细胞有显著的抑制作用，但对正常的人胚肾293A细胞没有明显的细胞毒性作用。
（2）丹参酮ⅡA可诱导肾细胞癌786-O细胞周期S期阻滞。其分子机制为：丹参酮ⅡA诱导肾细胞癌786-O细胞p53及其转录调控靶基因p21上调，且p53通过转录上调p21蛋白表达水平，参与介导丹参酮ⅡA诱导肾细胞癌786-O细胞周期S期阻滞。
（3）丹参酮ⅡA可进一步诱导肾细胞癌786-O细胞凋亡。在此过程中，p53转录下游靶基因Fas没有变化，而bax上调，凋亡效应蛋白caspase-3上调，表明bax参与丹参酮ⅡA诱导的肾细胞癌786-O细胞凋亡，丹参酮ⅡA诱导的肾细胞癌786-O细胞凋亡是通过线粒体途径，而非循Fas通道。
（4）丹参酮ⅡA处理肾细胞癌786-O细胞，可使其核仁蛋白NPM从核仁穿梭到核浆，且NPM和p53发生相互作用，表明NPM参与p53翻译后调控，维持了p53的稳定性，从而使p21蛋白表达水平上调。
本研究不但证明了丹参酮ⅡA可有效地抑制肾细胞癌786-O细胞生长增殖，并诱导细胞发生周期阻滞以至凋亡，还通过分子实验数据揭示了丹参酮ⅡA处理肾细胞癌786-O细胞通过驱动NPM从细胞核仁穿梭到核浆，使与核浆定位的p53发生共定位，进而增强NPM和p53相互作用，促进p53稳定性，继而转录激活其下游靶基因p21和bax蛋白水平上调的抑癌作用机制。并通过对正常人胚肾293A细胞的作用研究，证明丹参酮ⅡA可在基本不影响正常细胞情况下起肿瘤抑制作用，对有关肿瘤治疗的研究可起重要指导作用。
[Background]
Renal cell carcinoma (RCC), the most common cancer arising from the renalparenchyma, causes prevalent deaths worldwide and its incidence continues to rise. Althoughseveral therapeutic approaches have been applied to the treatment of RCC, including surgery,immunological therapies and vaccine treatment, further improvements are still needed.Therefore, it is extremely necessary to explore and develop new anti-cancer drugs. Notably,Traditional Chinese Medicine (TCM) draws much attention due to its dramatic roles in cancertherapy with the characteristics of low-toxicity and specificity, etc. Tanshinone ⅡA (Tan ⅡA),one of the phytochemical compounds isolated from the Chinese medicinal herb Danshen (rootof Salvia miltiorrhiza Bunge), possesses antioxidant and anti-aging properties. At present, TanⅡA has become a research hotspot, because it’s anti-cancer activity. However, the effect ofTan ⅡA on human RCC and its molecular mechanism need to be clarified.
[Objective]
Therefore, we aim to investigate the apoptotic effect of Tan ⅡA on human RCC786-Ocells and unveil the molecular mechanism by which it functions. Specifically, the viability of786-O cells following Tan ⅡA treatment was examined at first. Further, we delved into thesignaling pathways plus molecular mechanism by which Tan ⅡA induced786-O cell cyclearrest and apoptosis.
[Methods]
The viability of the786-O cells treated with Tan ⅡA (0μg/mL,1μg/mL,2μg/mL,4μg/mL and8μg/mL) was measured by MTT assay. As a comparison, human embryonickidney (HEK)293A cells were also treated with Tan ⅡA（0μg/mL,1μg/mL,2μg/mL,4μg/mL,8μg/mL,10μg/mL,20μg/mL,30μg/mL and40μg/mL）for24h and then subjectedto MTT assay. To demonstrate the growth inhibition of786-O cells induced by Tan ⅡA, thecell cycle distribution of786-O cells treated with and without Tan ⅡA was analyzed usingFlow cytometry (PI staining). To confirm cell cycle profile, the level of cyclin A proteinwhich is active in the S phase was subjected to western blot (WB). Moreover, to illustrate the molecular mechanism underlying cell cycle arrest, the expression levels of p21and p53whichare related with cell cycle checkpoints were determined by WB. On the other hand, TanⅡA-induced apoptosis was assessed through Flow cytometry (Annevin V/PI staining).Thereafter, the expression levels apoptosis-related molecules including Fas and bax which aretranscriptionally activated by p53and caspase-3which is an apoptotic executor wereexamined by WB. In order to reveal the molecular mechanism of p53up-regulation, the levelof MDM2protein which is a p53negative regulator was tested by WB. At last, a plasmidcontaining GFP-tagged NPM was constructed, and its sub-cellular localization was checkedby confocal microscope after its transfection in786-O cells. The physical interaction betweenNPM and p53was confirmed via co-immnunoprecipitation.
[Results]
(1) The MTT assay indicated that Tan ⅡA treatment for24h induced a marked inhibition ofthe growth of786-O cells. The half maximal inhibitory concentration (IC50) value forTan ⅡA treated786-O were estimated to be2μg/mL, whereas that for the Tan ⅡAtreated293A was8μg/mL.
(2) When786-O cells were treated with Tan ⅡA (0,2,4and8μg/ml) for24h, Flowcytometry analysis (PI stain) showed that the percentages of786-O cells in S-phasewere10.0%,11.5%,20.4%and23.3%, respectively. WB indicated that Tan ⅡA induceda dose-dependent upregulation of cyclin A. At the same time, p53and its downstreamgene p21were also increased in Tan ⅡA treated786-O cells, in a dose-dependentmanner.
(3) Following the treatment of786-O cells for24h with Tan ⅡA (2,4and8μg/mL), thenumber of early apoptotic cells increased from8.6(control) to27.2,27.8and28.8%,respectively. While the number of late apoptotic cells respectively increased from2.9(control) to9.2,12.5and13.9%. The total percentage of apoptotic cells was directlyrelated to the Tan ⅡA concentration, increased from11.5%(control) to36.4,40.3and42.7%. Tan ⅡA treatment resulted in a significant dose-dependent increase in the levelof bax and caspase-3.
(4) WB showed no change in the level of MDM2protein which is a negative regulator ofp53. Confocal microscopy showed that Tan ⅡA treatment resulted in a nucleoplasmictranslocation of GFP-tagged NPM from nucleolus. Co-immunoprecipitation tested thatthere was physical interaction between NPM and p53.
[Conclusion]
(1) Tan ⅡA treatment can cause significant dose-dependent inhibition of786-O cell growth,while Tan ⅡA treatment results in minor cytotoxicity on293A cells.
(2) Tan ⅡA treatment can induce S phase cell cycle arrest of786-O cells. The molecularmechanism can be illustrated by the upregulation of p53and its transcriptional targetgene p21, which are involved in S phase cell cycle arrest of786-O cells induced by TanⅡA treatment.
(3) Tan ⅡA treatment can further induce human RCC786-O cell apoptosis. In the apoptotic786-O cells treated with Tan ⅡA, the level of Fas proteins expression shows no change,in contrast, the expression level of bax protein increases. As a result, there is anupregulation of the apoptotic executor caspase-3. These data indicate that bax isinvolved in Tan ⅡA-induced cell apoptosis; Tan ⅡA-induced apoptosis is through amitochondrial pathway rather than Fas pathway.
(4) The translocation of Nucleolar protein NPM from nucleolus to nucleoplasm in786-Ocells after Tan ⅡA treatment and the physical interaction between NPM and p53indicates that NPM may be involved in the regulation of p53stability at apost-translational level, and ensuing upregulation of p21.
Our present study demonstrates that Tan ⅡA treatment can cause an effective growthinhibition and cell cycle arrest followed by apoptosis in human RCC786-O cells. Tan ⅡAtreatment can also trigger the translocation of NPM from nucleolus to nucleoplasm.Subsequently, Nucleoplasmic NPM can enhance p53stability via direct interaction betweenthe two, as a result, the downstream targeted genes including p21and bax are upregulated. Itis remarkable that Tan ⅡA has reduced cycotoxicity on HEK293A cells comparing with786-O cells, which suggests that Tan ⅡA has mild side effect on normal cells. Our researchwill provide promising guideline for the tumor therapy.
引文
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