Tautomycetin对乳腺癌细胞增殖的抑制作用及机制
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摘要
Tautomycetin (TMC)最初是从土壤链霉菌中分离得到的具有抗真菌活性的聚酮化合物。近几年又发现,TMC是蛋白磷酸酶PP1特异性抑制剂,具有免疫抑制活性,并且可以特异性抑制结肠癌细胞生长。但是,TMC抑制肿瘤细胞生长是否与其抑制PP1活性相关未得到证明,抑制肿瘤细胞生长的机制还未详细阐明。我们的前期实验发现TMC并不是特异性抑制结肠癌细胞生长,它对乳腺癌等多种细胞系具有显著生长抑制作用。
本研究阐明了TMC的肿瘤细胞生长抑制活性与PP1抑制活性之间是否相关,并重点研究了TMC抑制乳腺癌细胞生长的信号通路,具体研究结果及结论如下：
(1)采用MTT和磷酸酶PP1活性测定等方法,测定TMC及其不同衍生物的磷酸酶PP1抑制、肿瘤细胞生长抑制和免疫抑制活性。结果显示：多个衍生物具有较强的PP1抑制活性,却没有显著的肿瘤细胞生长抑制和免疫抑制活性；而部分衍生物具有较强的肿瘤细胞生长抑制活性,PP1抑制活性却不显著；TMC1μmol/L和衍生物TMC-F150μmol/L都能抑制MCF-7细胞内PP160%的活性,而对MCF-7细胞增殖的抑制率分别为90%和24%。表明TMC的肿瘤细胞生长抑制与免疫抑制活性不是通过其蛋白磷酸酶PP1抑制活性实现的。
(2)采用MTT、Transwell细胞迁移和侵袭实验和流式细胞术等方法检测TMC对MCF-7细胞增殖、侵袭和凋亡的影响。结果显示：TMC抑制MCF-7细胞增殖的ICso值为0.36μmol/L; TMC0.4μmol/L抑制MCF-7细胞迁移率和侵袭率分别为76%和79%；TMC0.5μmol/L诱导MCF-7细胞早期凋亡和晚期凋亡的比率分别为21%和34%；Western blotting检测TMC对凋亡相关蛋白表达。结果显示：TMC可以显著降低Bcl-2表达量和Bad磷酸化水平,提高Bax表达量和cytochrome-c线粒体释放量,caspase-9和caspase-7被活化。以上结果表明,TMC通过调控Bcl-2家族,依赖线粒体/细胞色素c介导的凋亡信号激活下游caspase级联通路,最终诱导MCF-7细胞凋亡。
(3)采用MTT、流式细胞术和Western blotting等方法,检测TMC对耐阿霉素乳腺癌细胞MCF-7/ADR细胞增殖等影响。结果显示：TMC抑制MCF-7/ADR细胞生长的ICso值为1.26μmol/L; TMC1μmol/L诱导MCF-7细胞早期凋亡和晚期凋亡的比率分别为17.2%和28.4%；TMC同样可以显著降低Bcl-2蛋白表达量,激活caspase-9和caspase-7o以上结果表明,TMC对MCF-7/ADR细胞同样敏感,并通过依赖线粒体/细胞色素c介导凋亡通路诱导MCF-7/ADR细胞凋亡。
(4)采用Western blotting、双荧光素酶报告基因等实验检测TMC对MAPK (ERK、p-38和JNK)、Wnt、p53和Akt信号通路相关蛋白磷酸化和转录因子活性的影响。发现TMC可以显著降低Akt及其下游调控蛋白FKHR的磷酸化,并且0.4μmol/L TMC使Akt下游调控的转录因子CREB转录活性降低70%；TMC同时可以显著抑制上游直接调控Akt的PDK1激酶磷酸化,但是对EGFR和HER2酪氨酸激酶受体磷酸化无显著影响。进一步观察转染Akt持续激活质粒myr-Akt对TMC抑制MCF-7增殖的影响。结果显示：0.5μmol/L TMC对转染空载体和myr-Akt质粒的MCF-7细胞的增殖抑制率分别为64%和31%。以上结果表明,TMC通过阻断MCF-7细胞中Akt信号通路,从而调控下游细胞生存和凋亡相关蛋白及转录因子活性。
(5)通过siRNA技术将PP1基因沉默,检测对Akt磷酸化的影响。结果显示：PP1基因沉默并没有显著影响Akt激酶的磷酸化水平。以上结果进一步表明TMC抑制MCF-7细胞增殖与其抑制PP1活性无主要关联。
(6)采用MTT、Western blotting和细胞转染等方法,检测TMC与Leptomycin B (LMB)联合用药是否具有协同效应及其机制。结果显示：LMB先加24h再加TMC共同作用协同效应较好,协同效应指数CI值为0.38-0.49；联合用药达到半数抑制时,TMC和LMB的用量分别为单独用药时的23.8%和17.7%；TMC和LMB联用可以增强TMC对Akt和FKHR等蛋白磷酸化的下调作用；LMB可以增强TMC诱导的FKHR细胞核聚集。以上结果表明,TMC与LMB联用对抑制MCF-7细胞增殖具有显著协同效应,协同效应与LMB促进TMC诱导的FKHR细胞核聚集有关联。
综上,论文研究发现TMC的抗肿瘤活性与PP1抑制活性之间的相关性较低；阐明了TMC诱导MCF-7细胞凋亡的机制；证明Akt和FKHR抑制剂类药物与核输出抑制剂联用具有协同效应。研究工作为TMC药物机制提供了新的例证,为进一步确定TMC抗肿瘤的直接作用靶点奠定了基础；同时,为TMC联合用药提供了一个新的设计思路。
Tautomycetin (TMC) is polyketide natural product originally isolated as antifungal antibiotics from Streptomyces griseochromogens. TMC was later found to be able to specifically inhibit protein phosphatase type1(PP1). TMC has been also identified as a potent immunosuppressor and a potential drug for colorectal cancer. The anticancer activities of TMC are both thought to be related to its ability to inhibit protein phosphatases. Unfortunately, this hypothesis has not yet been fully clarified. Our studies showed that TMC could inhibit proliferation of different kinds of cancer cells in vitro.
In this study, we presented the correlation between the anti-cancer activity of TMC and the inhibitory activity of PP1, with the focus on the signaling pathway of the anticancer activity of TMC. The main results and conclusions were listed as follows:
(1) Phosphatase inhibition, immunosuppressive and anticancer activities of TMC and its analogues were determinded. The results showed that some analogues of TMC exhibited strong PP1-inhibiting activity rather than anti-tumor activity and immunosuppressive activity; some analogues exhibited cytotoxic activity rather than PP1-inhibiting activity. TMC (1μmol/L) and TMC-F1(50μmol/L) could both inhibited PPl activity in MCF-7cell lines by60%, but with90%and24%inbibiting percentages of MCF-7cell proliferation, respectively. Therefore, the anti-tumor activity and immunosuppressive activity were not correlated with the inhibitory activity of protein phosphatase PP1.
(2) The effects of TMC on the MCF-7cell proliferation, invasion and apoptosis were examined by MTT, cell invasion assays and flow cytometry analysis, respectively. The estimated IC50value was0.36umol/L in MCF-7cell lines; the percentages of cell migration and invasion of MCF-7cell lines inhibiting by0.4μmol/L TMC were76%and79%, respectively; the percentages of MCF-7cell early and advanced apoptosis induced by0.5μmol/L TMC were21%and34%, respectively. Furthermore, we examined the effects of TMC on the apoptosis relative protein expression by western blotting. The results indicated that the expression level of Bcl-2and phosphorylation of Bad were both decreased, expression of Bax and mitochondria release of cytochrome-c were enhanced, caspase-9and caspase-7were activated by TMC treatment. Therefore, it was argued that TMC could activate caspase cascade pathway through the regulations of Bcl-2family and mitochondrial/cytochrome-c mediated apoptosis pathway, which could induce the apoptosis of MCF-7cells.
(3) Detecting the influence of TMC on Adriamycin resistant human breast adenocarcinoma MCF-7/ADR cells by MTT and Western blotting. The results showed that TMC inhibited the proliferation of MCF-7/ADR cells with the IC50values being1.26μmol/L. The early and late apoptosis rate of MCF-7/ADR cells induced by1μmol/L TMC increased to17.2%and28.4%, respectively. Similarly. TMC could significantly decrease the phosphorylation of Akt in MCF-7/ADR cells and the expression of Bcl-2. while activate caspase-9and caspase-7. It indicated that TMC is sensitive to MCF-7/ADR cells and could activate caspase cascade pathway through the regulations of Bcl-2family and mitochondrial/cytochrome-c mediated apoptosis pathway, which could induce the apoptosis of MCF-7/ADR cells.
(4) The effects of TMC on the relative protein phosphorylations and transcription factor activities of MAPK (ERK. p-38and JNK), Wnt. p53and Akt signal pathway were examined by Western blotting and dual luciferase assay system. The results showed that the phosphorylation of Akt and its downstream target FKHR were decreased significantly, and the transcription activity of CREB were also decreased by70%. Meanwhile, the phosphorylation of kinase PDK1was inhibited by TMC, but those of tyrosine kinase EGFR and HER2were not. Next, we examined the role of Akt in TMC-mediated inhibition. We found that TMC inhibited proliferation of MCF-7cells transfected with blank vector and myr-Akt plasmid by64%and31%, respectively. We demonstrated that TMC inhibited Akt and its downstream signaling, subsequently resulting in apoptosis of MCF-7cells.
(5) The gene PP1was silenced by siRNA technology, then the influence on phosphorylation of Akt was detected and no significant change was observed. It was further indicated that the inhibitory of TMC on MCF-7was not clearly correlated with the inhibition of PP1.
(6) To investigate whether there is synergistic effect between TMC and Leptomycin B (LMB), MTT, Western blotting and Cell transfection assays were conducted. The results showed that the synergistic effect was better by adding LMB first and TMC was added24h later, with a CI value0.38-0.49. In combination treatment, the required dosage of TMC and LMB for half-inhibition is reduced to23.8%and17.7%compared to single treatment. LMB could enhance the down-regulating effect of TMC on phosphorylation of Akt and FKHR. LMB could also enhance the gathering of nuclear induced by TMC. It was implied that combination treatment of TMC and LMB has notable synergistic effect on the inhibitory of MCF-7cell growth. The effect may be related to the function of LMB to promote the nuclear gathering which is induced by TMC.
In summary, our results indicated that cytotoxicity of TMC was not associated with its PP1inhibition activity. Moreover, we provided a plausible mechanism of TMC inducing the MCF-7cell apoptosis and proved that there was a synergistic antitumor activity of Akt inhibitors combined with nuclear export inhibitors. The results of this study proposed a new paradigm for investigating the mechanism of the anti-tumor drugs which inhibit protein phosphatase, laid the foundation for further identifying the direct target of its anti-tumor activity. Lastly, our study provided a new design strategy for rational drug combination.
本研究阐明了TMC的肿瘤细胞生长抑制活性与PP1抑制活性之间是否相关,并重点研究了TMC抑制乳腺癌细胞生长的信号通路,具体研究结果及结论如下：
(1)采用MTT和磷酸酶PP1活性测定等方法,测定TMC及其不同衍生物的磷酸酶PP1抑制、肿瘤细胞生长抑制和免疫抑制活性。结果显示：多个衍生物具有较强的PP1抑制活性,却没有显著的肿瘤细胞生长抑制和免疫抑制活性；而部分衍生物具有较强的肿瘤细胞生长抑制活性,PP1抑制活性却不显著；TMC1μmol/L和衍生物TMC-F150μmol/L都能抑制MCF-7细胞内PP160%的活性,而对MCF-7细胞增殖的抑制率分别为90%和24%。表明TMC的肿瘤细胞生长抑制与免疫抑制活性不是通过其蛋白磷酸酶PP1抑制活性实现的。
(2)采用MTT、Transwell细胞迁移和侵袭实验和流式细胞术等方法检测TMC对MCF-7细胞增殖、侵袭和凋亡的影响。结果显示：TMC抑制MCF-7细胞增殖的ICso值为0.36μmol/L; TMC0.4μmol/L抑制MCF-7细胞迁移率和侵袭率分别为76%和79%；TMC0.5μmol/L诱导MCF-7细胞早期凋亡和晚期凋亡的比率分别为21%和34%；Western blotting检测TMC对凋亡相关蛋白表达。结果显示：TMC可以显著降低Bcl-2表达量和Bad磷酸化水平,提高Bax表达量和cytochrome-c线粒体释放量,caspase-9和caspase-7被活化。以上结果表明,TMC通过调控Bcl-2家族,依赖线粒体/细胞色素c介导的凋亡信号激活下游caspase级联通路,最终诱导MCF-7细胞凋亡。
(3)采用MTT、流式细胞术和Western blotting等方法,检测TMC对耐阿霉素乳腺癌细胞MCF-7/ADR细胞增殖等影响。结果显示：TMC抑制MCF-7/ADR细胞生长的ICso值为1.26μmol/L; TMC1μmol/L诱导MCF-7细胞早期凋亡和晚期凋亡的比率分别为17.2%和28.4%；TMC同样可以显著降低Bcl-2蛋白表达量,激活caspase-9和caspase-7o以上结果表明,TMC对MCF-7/ADR细胞同样敏感,并通过依赖线粒体/细胞色素c介导凋亡通路诱导MCF-7/ADR细胞凋亡。
(4)采用Western blotting、双荧光素酶报告基因等实验检测TMC对MAPK (ERK、p-38和JNK)、Wnt、p53和Akt信号通路相关蛋白磷酸化和转录因子活性的影响。发现TMC可以显著降低Akt及其下游调控蛋白FKHR的磷酸化,并且0.4μmol/L TMC使Akt下游调控的转录因子CREB转录活性降低70%；TMC同时可以显著抑制上游直接调控Akt的PDK1激酶磷酸化,但是对EGFR和HER2酪氨酸激酶受体磷酸化无显著影响。进一步观察转染Akt持续激活质粒myr-Akt对TMC抑制MCF-7增殖的影响。结果显示：0.5μmol/L TMC对转染空载体和myr-Akt质粒的MCF-7细胞的增殖抑制率分别为64%和31%。以上结果表明,TMC通过阻断MCF-7细胞中Akt信号通路,从而调控下游细胞生存和凋亡相关蛋白及转录因子活性。
(5)通过siRNA技术将PP1基因沉默,检测对Akt磷酸化的影响。结果显示：PP1基因沉默并没有显著影响Akt激酶的磷酸化水平。以上结果进一步表明TMC抑制MCF-7细胞增殖与其抑制PP1活性无主要关联。
(6)采用MTT、Western blotting和细胞转染等方法,检测TMC与Leptomycin B (LMB)联合用药是否具有协同效应及其机制。结果显示：LMB先加24h再加TMC共同作用协同效应较好,协同效应指数CI值为0.38-0.49；联合用药达到半数抑制时,TMC和LMB的用量分别为单独用药时的23.8%和17.7%；TMC和LMB联用可以增强TMC对Akt和FKHR等蛋白磷酸化的下调作用；LMB可以增强TMC诱导的FKHR细胞核聚集。以上结果表明,TMC与LMB联用对抑制MCF-7细胞增殖具有显著协同效应,协同效应与LMB促进TMC诱导的FKHR细胞核聚集有关联。
综上,论文研究发现TMC的抗肿瘤活性与PP1抑制活性之间的相关性较低；阐明了TMC诱导MCF-7细胞凋亡的机制；证明Akt和FKHR抑制剂类药物与核输出抑制剂联用具有协同效应。研究工作为TMC药物机制提供了新的例证,为进一步确定TMC抗肿瘤的直接作用靶点奠定了基础；同时,为TMC联合用药提供了一个新的设计思路。
Tautomycetin (TMC) is polyketide natural product originally isolated as antifungal antibiotics from Streptomyces griseochromogens. TMC was later found to be able to specifically inhibit protein phosphatase type1(PP1). TMC has been also identified as a potent immunosuppressor and a potential drug for colorectal cancer. The anticancer activities of TMC are both thought to be related to its ability to inhibit protein phosphatases. Unfortunately, this hypothesis has not yet been fully clarified. Our studies showed that TMC could inhibit proliferation of different kinds of cancer cells in vitro.
In this study, we presented the correlation between the anti-cancer activity of TMC and the inhibitory activity of PP1, with the focus on the signaling pathway of the anticancer activity of TMC. The main results and conclusions were listed as follows:
(1) Phosphatase inhibition, immunosuppressive and anticancer activities of TMC and its analogues were determinded. The results showed that some analogues of TMC exhibited strong PP1-inhibiting activity rather than anti-tumor activity and immunosuppressive activity; some analogues exhibited cytotoxic activity rather than PP1-inhibiting activity. TMC (1μmol/L) and TMC-F1(50μmol/L) could both inhibited PPl activity in MCF-7cell lines by60%, but with90%and24%inbibiting percentages of MCF-7cell proliferation, respectively. Therefore, the anti-tumor activity and immunosuppressive activity were not correlated with the inhibitory activity of protein phosphatase PP1.
(2) The effects of TMC on the MCF-7cell proliferation, invasion and apoptosis were examined by MTT, cell invasion assays and flow cytometry analysis, respectively. The estimated IC50value was0.36umol/L in MCF-7cell lines; the percentages of cell migration and invasion of MCF-7cell lines inhibiting by0.4μmol/L TMC were76%and79%, respectively; the percentages of MCF-7cell early and advanced apoptosis induced by0.5μmol/L TMC were21%and34%, respectively. Furthermore, we examined the effects of TMC on the apoptosis relative protein expression by western blotting. The results indicated that the expression level of Bcl-2and phosphorylation of Bad were both decreased, expression of Bax and mitochondria release of cytochrome-c were enhanced, caspase-9and caspase-7were activated by TMC treatment. Therefore, it was argued that TMC could activate caspase cascade pathway through the regulations of Bcl-2family and mitochondrial/cytochrome-c mediated apoptosis pathway, which could induce the apoptosis of MCF-7cells.
(3) Detecting the influence of TMC on Adriamycin resistant human breast adenocarcinoma MCF-7/ADR cells by MTT and Western blotting. The results showed that TMC inhibited the proliferation of MCF-7/ADR cells with the IC50values being1.26μmol/L. The early and late apoptosis rate of MCF-7/ADR cells induced by1μmol/L TMC increased to17.2%and28.4%, respectively. Similarly. TMC could significantly decrease the phosphorylation of Akt in MCF-7/ADR cells and the expression of Bcl-2. while activate caspase-9and caspase-7. It indicated that TMC is sensitive to MCF-7/ADR cells and could activate caspase cascade pathway through the regulations of Bcl-2family and mitochondrial/cytochrome-c mediated apoptosis pathway, which could induce the apoptosis of MCF-7/ADR cells.
(4) The effects of TMC on the relative protein phosphorylations and transcription factor activities of MAPK (ERK. p-38and JNK), Wnt. p53and Akt signal pathway were examined by Western blotting and dual luciferase assay system. The results showed that the phosphorylation of Akt and its downstream target FKHR were decreased significantly, and the transcription activity of CREB were also decreased by70%. Meanwhile, the phosphorylation of kinase PDK1was inhibited by TMC, but those of tyrosine kinase EGFR and HER2were not. Next, we examined the role of Akt in TMC-mediated inhibition. We found that TMC inhibited proliferation of MCF-7cells transfected with blank vector and myr-Akt plasmid by64%and31%, respectively. We demonstrated that TMC inhibited Akt and its downstream signaling, subsequently resulting in apoptosis of MCF-7cells.
(5) The gene PP1was silenced by siRNA technology, then the influence on phosphorylation of Akt was detected and no significant change was observed. It was further indicated that the inhibitory of TMC on MCF-7was not clearly correlated with the inhibition of PP1.
(6) To investigate whether there is synergistic effect between TMC and Leptomycin B (LMB), MTT, Western blotting and Cell transfection assays were conducted. The results showed that the synergistic effect was better by adding LMB first and TMC was added24h later, with a CI value0.38-0.49. In combination treatment, the required dosage of TMC and LMB for half-inhibition is reduced to23.8%and17.7%compared to single treatment. LMB could enhance the down-regulating effect of TMC on phosphorylation of Akt and FKHR. LMB could also enhance the gathering of nuclear induced by TMC. It was implied that combination treatment of TMC and LMB has notable synergistic effect on the inhibitory of MCF-7cell growth. The effect may be related to the function of LMB to promote the nuclear gathering which is induced by TMC.
In summary, our results indicated that cytotoxicity of TMC was not associated with its PP1inhibition activity. Moreover, we provided a plausible mechanism of TMC inducing the MCF-7cell apoptosis and proved that there was a synergistic antitumor activity of Akt inhibitors combined with nuclear export inhibitors. The results of this study proposed a new paradigm for investigating the mechanism of the anti-tumor drugs which inhibit protein phosphatase, laid the foundation for further identifying the direct target of its anti-tumor activity. Lastly, our study provided a new design strategy for rational drug combination.
引文
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