蛋白酶抑制剂的筛选及其生物活性研究
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摘要
目前,越来越多的研究显示,蛋白水解酶的活性紊乱与众多疾病相关,蛋白酶活性调控对于治疗相关疾病具有重要的作用。
最新研究显示,自噬和凋亡是两种重要的细胞行为,在生理和病理水平中都具有重要作用。据报道,在自噬和凋亡过程中,半胱氨酸蛋白酶家族的溶酶体组织蛋白酶(cathepsin)和半胱氨酸-天冬氨酸蛋白酶(caspase)发挥重要作用。本论文应用生物化学和细胞生物学等研究手段,以cathepsin为靶点,成功的筛选出能够抑制cathepsin和caspase的抑制剂丹参酮ⅡA磺酸钠(STS)。同时,我们对这种化合物在自噬和凋亡的活性调控方面进行了研究。我们应用血清去除的方法诱导了HT1080细胞的自噬和凋亡,并在此过程中,溶酶体膜通透性发生明显的变化。STS能够有效的降低溶酶体膜通透性的变化,并抑制这种血清去除诱导的自噬和凋亡。STS可以通过抑制半胱氨酸酶的活性来抑制细胞的自噬,但是它不能够通过调控caspase的活性来抑制caspase依赖的细胞凋亡。同时STS也能够抑制聚二磷酸腺苷核糖多聚酶(PARP)的降解。最后,根据我们的试验结果,我们推测STS能够通过抑制LMP的增加来调控细胞的凋亡,并通过半胱氨酸酶的抑制来抑制自噬反应。
同时,由于cathepsin在肿瘤的迁移和侵袭过程中的重要作用,本论文也在另一方面证明了STS通过调控细胞外cathepsin的活性来抑制肿瘤细胞的迁移和侵袭。
除了半胱氨酸蛋白酶外,基质金属蛋白酶(MMP)也是一类重要的蛋白水解酶。对其活性的调控对于相关疾病的治疗具有重要意义。研究显示,中药对于治疗MMP活性异常的疾病具有显著的效果。目前中药的治疗被认为是一种多靶点共同作用的结果,因此,确定中药在疾病中的治疗靶点对于我们研究中药的治疗作用具有重要意义。本论文中以MMP为靶点,应用生物化学与细胞生物学的研究方法,对中药治疗肿瘤的靶点进行研究,并成功证明了一些中药在治疗肿瘤中的部分作用机理。为中药治疗肿瘤的机理研究提供了重要的依据,同时也为MMP抑制剂的筛选提供了天然产物来源。
本论文的创新之处在于丹参酮ⅡA磺酸钠(STS)对caspase和cathepsin的抑制作用到目前还未曾有人报道,并且关于STS抑制自噬的研究也同样未曾报道。同时,本论文也提出了STS在肿瘤迁移和侵袭方面的作用。本论文所提出的STS的新作用靶点,可能促使STS在应用方面有新的突破。另外本论文中应用MMP靶点对中药的作用机理进行研究,也为中药的治疗机理的研究和中药中抗癌成分的开发提供了一种新的方法,对于中药研究具有一定的参考价值。
Both cysteine protease and MMP are important members of proteinase family. Studies have shown that the disorders of these proteinases activities are associated with many diseases, and the regulation of activities will contribute to the treatment of related diseases. The development of Protease inhibitor plays an important role for the effective regulation of protease activity in abnormal cells, and the regulation of proteinase activity disorders by proteinase inhibitor have become the treatment of related diseases. In another hand, the development of special inhibitors would contribute to the research of protease function
Autophagy is regarded as a cellular self-protective mechanism and keeps cells survival. during nutrient and growth factor deprivation and other stressful conditions. However, apoptosis is a programmed cell death mechanism that occurrence in physiological and pathological conditions. The current studies shown, in many cases, both apoptosis and autophagy were coexistence in several cell death processes notwithstanding the converse mechanism. Based mostly on the growing evidence that there must be a interconnection between autophagy an apoptosis, and this interconnection regulated survival or death of cells. So far, the regulatory mechanism of between autophagy and apoptosis was not clear.
According to the reported, cysteine cathepsins (cathepsins) are involved in apoptosis and autophagic cell death. In the apoptosis pathway, cathepsins not only regulate apoptosis by the degradation of Bcl-2 family members, but also promote apoptosis through the activation of the procaspase. For the regulation of autophagy, lysosomal cathepsins play an important role in the ececution autophagy, and the inhibition of cathepsins activities can effectively control the occurrence of autophagy. At present, the interaction between apoptosis and autophagy is a matter of debate in different scientific communities, and the relationship need for more experiments to prove. Since cathepsins play important role in both Physiological and pathological processes, they may act as integrators of the two types of programmed cell death. the regulation of activities will control the development of autophagy and apoptosis and contribute to the treatment of related diseases.
In this paper, cathepsin L is chosen as the target for inhibitors screening. We found that Sodium Tanshinone IIA Sulfonate (STS) can inhibit cathepsin L in vitro significantly. The inhibition activities of STS on cathepsin B, C and K are also detected, while the inhibitory effect is moderate. Furthermore, the inhibitory of STS on cathepsin L is time-dependent. Moreover, we also examined the inhibition of STS on caspase-3 and-8 which are cysteine proteinase, and play crucial role in apoptosis.
Increasing evidence indicate that both cathepsins and caspases involved in the regulation machinery of cell death. In view of the inhibitory of STS on these cysteine proteinases, we wonder whether STS can regulate autophagy an apoptosis by the inhibition of these cysteine proteinases, especially in apoptosis accompany autophagy. Therefore, serum starvation was used to induce HT1080 cell death. In this model, Lysosomal Membrane Permeabilization (LMP), the enhancement of autophagic activity, the up-regulation of PARP degradation (which is a substrate of caspase-3) and.cell apoptosis were detected. These results proved serum deprivation induced autopahgy, and apoptosis. After treated this model with STS, LMP, the transition of LC3-Ⅰto LC3-Ⅱand the degradation of PARP were all reduced and apoptosis was inhibited. Surprisingly, the transition of LC3-Ⅰto LC3-Ⅱwas reduced at 48 hours compared with 36 hours after serum deprivation. We presumed that cells exerted cytoprotective effect to keep alive at early serum deprivation, however, when excessive autophagy can not against long-time nutritional deficiency, cells executed apoptosis to replace autophagy. STS regulated autophagy to prevent occurrence of excessive autophagy, and delay apoptosis.
Because both apoptosis and autophagy are involved in this model, in order to further clarify the function of STS in vivo, we have exmained pan-caspase inhibitor (zVAD-fmk) and broad-spectrum cysteine proteinase inhibitors (E-64 and E-64d) by using this model. The result that zVAD-fmk can not inhibit apoptosis effectively demonstrated the apoptosis induced by serum deprivation is predominate caspase independent apoptosis and can not be regulated effectively by the inhibition of caspase activities. So, we ascertained STS carried out the inhibition of apoptosis by targeting other pathway. Meanwhile, E-64d inhibits autophagy and promotes apoptosis. This means autophagy is a cytoprotective mechanism, and the inhibition of autophagy promotes the development of apoptosis. However, E-64 can not impact the development of apoptosis. We conjectured that may be due to the poor membrane permeability of E-64. These results demonstrate STS regulate other unknown target rather then caspase to inhibit apoptosis induced by serum deprivation. In order to determine whether inhibition of STS on caspase can regulate apoptosis, cisplatin-induced caspase-dependent apoptosis was tested. The results showed that STS could not inhibit caspase-dependent apoptosis, but zVAD-fmk as a positive control effectively inhibited caspase-dependent apoptosis. These results documented that the inhibition of caspase by STS is insufficient to inhibit caspase-dependent apoptosis.
It was reported lysosomal membrane permeability (LMP) was shown to be involved in cell autophagy and apoptosis. Therefore, our experiment also examined changes of LMP. After serum deprivation, the increase of LMP was detected, and STS can decrease the level of increased LMP. However, neither cysteine proteinase inhibitors (E-64 and E-64d) nor caspase inhibitor (zVAD-fmk) can inhibit increased LMP. So we can determine the change of LMP is not related to cysteine proteinase activities. Meanwhile, the inhibition of autophagy by E-64d could not decrease LMP, this mean LMP is the upstream of autophagy or there was not relationship between LMP and autophagy. Increasing evidences indicate LMP can regulate caspase-dependent and caspase-independent apoptosis, we presumed STS inhibited the increase of LMP to inhibit caspase-independent apoptosis.
In addition, in our experiment, the degradation of poly ADP-ribose polymerase (PARP) was detected to determent the activity of caspase-3. However, we surprisedly detected there are considerable degradation of PARP notwithstanding the apoptosis induced by serum deprivation is a caspase independent apoptosis, and STS could inhibit effectively the degradation of PARP. According to recent researches, many cysteine proteases degraded PARP to different molecular weight. So, we presumed STS inhibit the degradation of PARP by the inhibition of cysteine protease.
We also detected the ability of asparagines which inhibit autophagic-lysosomal delivery serum deprivation induced apoptosis and autophagy on autophagy and apoptosis induced by serum deprivation. Asparagine can inhibit LMP and apoptosis, but this result contrary to the effect of E-64d on serum deprivation induced apoptosis. Autophagy is generally considered to be a cellular protective mechanism, so we presumed that large concentration of STS (10mM) could target to other unknown pathway to regulate apoptosis.
In summary, the serum deprivation-induced apoptosis is a caspase independent apoptosis with autophagy, and the inhibition of autophagy promotes apoptosis. The inhibition of autophagy by STS is through the regulation of cysteine proteases activities. Meanwhile, we presumed the inhibition of apoptosis is through the regulation of LMP.
In addition to the regulation of apoptosis and autophagy, cathepsin is also involved in the development of tumor cells. It is reported that cathepsins promote tumor cell migration and invasion through the degradation of extracellular matrix components and adhesion-related proteins. Yoko Hashimoto and his colleagues demonstrate that approximately 10-fold higher mature cathepsin L activity was secreted in a medium of human fibrosarcoma (HT 1080) cells, compared with their intracellular activity and speculate that the cathepsin L found in HT1080 cell medium is involved in cancer invasion and metastasis. Therefore, we have investigated the inhibitory effect of STS and E-64 on HT1080 cell migration and invasion. The results showed that STS and E-64 could inhibit HT1080 cell migration and invasion effectively.
Further more, matrix metalloproteinase (MMP) is chosen as target for inhibitor screening. Traditional Chinese medicine (TCM) has a significant effect in the treatment of cancer, but the mechanism is not clear. We wonder to know whether TCM can inhibit MMP activity to treat cancer. So we screened MMP inhibitor from TCM. Stir-baked Fructus Gardeniae, Polygoni Multiflori Gaulis, and Ramulus Cinnamomi can inhibit MMP activity in vitro and regulate the cell behavior in vivo. Our findings will help to understand the mechanism of these TCM.
最新研究显示,自噬和凋亡是两种重要的细胞行为,在生理和病理水平中都具有重要作用。据报道,在自噬和凋亡过程中,半胱氨酸蛋白酶家族的溶酶体组织蛋白酶(cathepsin)和半胱氨酸-天冬氨酸蛋白酶(caspase)发挥重要作用。本论文应用生物化学和细胞生物学等研究手段,以cathepsin为靶点,成功的筛选出能够抑制cathepsin和caspase的抑制剂丹参酮ⅡA磺酸钠(STS)。同时,我们对这种化合物在自噬和凋亡的活性调控方面进行了研究。我们应用血清去除的方法诱导了HT1080细胞的自噬和凋亡,并在此过程中,溶酶体膜通透性发生明显的变化。STS能够有效的降低溶酶体膜通透性的变化,并抑制这种血清去除诱导的自噬和凋亡。STS可以通过抑制半胱氨酸酶的活性来抑制细胞的自噬,但是它不能够通过调控caspase的活性来抑制caspase依赖的细胞凋亡。同时STS也能够抑制聚二磷酸腺苷核糖多聚酶(PARP)的降解。最后,根据我们的试验结果,我们推测STS能够通过抑制LMP的增加来调控细胞的凋亡,并通过半胱氨酸酶的抑制来抑制自噬反应。
同时,由于cathepsin在肿瘤的迁移和侵袭过程中的重要作用,本论文也在另一方面证明了STS通过调控细胞外cathepsin的活性来抑制肿瘤细胞的迁移和侵袭。
除了半胱氨酸蛋白酶外,基质金属蛋白酶(MMP)也是一类重要的蛋白水解酶。对其活性的调控对于相关疾病的治疗具有重要意义。研究显示,中药对于治疗MMP活性异常的疾病具有显著的效果。目前中药的治疗被认为是一种多靶点共同作用的结果,因此,确定中药在疾病中的治疗靶点对于我们研究中药的治疗作用具有重要意义。本论文中以MMP为靶点,应用生物化学与细胞生物学的研究方法,对中药治疗肿瘤的靶点进行研究,并成功证明了一些中药在治疗肿瘤中的部分作用机理。为中药治疗肿瘤的机理研究提供了重要的依据,同时也为MMP抑制剂的筛选提供了天然产物来源。
本论文的创新之处在于丹参酮ⅡA磺酸钠(STS)对caspase和cathepsin的抑制作用到目前还未曾有人报道,并且关于STS抑制自噬的研究也同样未曾报道。同时,本论文也提出了STS在肿瘤迁移和侵袭方面的作用。本论文所提出的STS的新作用靶点,可能促使STS在应用方面有新的突破。另外本论文中应用MMP靶点对中药的作用机理进行研究,也为中药的治疗机理的研究和中药中抗癌成分的开发提供了一种新的方法,对于中药研究具有一定的参考价值。
Both cysteine protease and MMP are important members of proteinase family. Studies have shown that the disorders of these proteinases activities are associated with many diseases, and the regulation of activities will contribute to the treatment of related diseases. The development of Protease inhibitor plays an important role for the effective regulation of protease activity in abnormal cells, and the regulation of proteinase activity disorders by proteinase inhibitor have become the treatment of related diseases. In another hand, the development of special inhibitors would contribute to the research of protease function
Autophagy is regarded as a cellular self-protective mechanism and keeps cells survival. during nutrient and growth factor deprivation and other stressful conditions. However, apoptosis is a programmed cell death mechanism that occurrence in physiological and pathological conditions. The current studies shown, in many cases, both apoptosis and autophagy were coexistence in several cell death processes notwithstanding the converse mechanism. Based mostly on the growing evidence that there must be a interconnection between autophagy an apoptosis, and this interconnection regulated survival or death of cells. So far, the regulatory mechanism of between autophagy and apoptosis was not clear.
According to the reported, cysteine cathepsins (cathepsins) are involved in apoptosis and autophagic cell death. In the apoptosis pathway, cathepsins not only regulate apoptosis by the degradation of Bcl-2 family members, but also promote apoptosis through the activation of the procaspase. For the regulation of autophagy, lysosomal cathepsins play an important role in the ececution autophagy, and the inhibition of cathepsins activities can effectively control the occurrence of autophagy. At present, the interaction between apoptosis and autophagy is a matter of debate in different scientific communities, and the relationship need for more experiments to prove. Since cathepsins play important role in both Physiological and pathological processes, they may act as integrators of the two types of programmed cell death. the regulation of activities will control the development of autophagy and apoptosis and contribute to the treatment of related diseases.
In this paper, cathepsin L is chosen as the target for inhibitors screening. We found that Sodium Tanshinone IIA Sulfonate (STS) can inhibit cathepsin L in vitro significantly. The inhibition activities of STS on cathepsin B, C and K are also detected, while the inhibitory effect is moderate. Furthermore, the inhibitory of STS on cathepsin L is time-dependent. Moreover, we also examined the inhibition of STS on caspase-3 and-8 which are cysteine proteinase, and play crucial role in apoptosis.
Increasing evidence indicate that both cathepsins and caspases involved in the regulation machinery of cell death. In view of the inhibitory of STS on these cysteine proteinases, we wonder whether STS can regulate autophagy an apoptosis by the inhibition of these cysteine proteinases, especially in apoptosis accompany autophagy. Therefore, serum starvation was used to induce HT1080 cell death. In this model, Lysosomal Membrane Permeabilization (LMP), the enhancement of autophagic activity, the up-regulation of PARP degradation (which is a substrate of caspase-3) and.cell apoptosis were detected. These results proved serum deprivation induced autopahgy, and apoptosis. After treated this model with STS, LMP, the transition of LC3-Ⅰto LC3-Ⅱand the degradation of PARP were all reduced and apoptosis was inhibited. Surprisingly, the transition of LC3-Ⅰto LC3-Ⅱwas reduced at 48 hours compared with 36 hours after serum deprivation. We presumed that cells exerted cytoprotective effect to keep alive at early serum deprivation, however, when excessive autophagy can not against long-time nutritional deficiency, cells executed apoptosis to replace autophagy. STS regulated autophagy to prevent occurrence of excessive autophagy, and delay apoptosis.
Because both apoptosis and autophagy are involved in this model, in order to further clarify the function of STS in vivo, we have exmained pan-caspase inhibitor (zVAD-fmk) and broad-spectrum cysteine proteinase inhibitors (E-64 and E-64d) by using this model. The result that zVAD-fmk can not inhibit apoptosis effectively demonstrated the apoptosis induced by serum deprivation is predominate caspase independent apoptosis and can not be regulated effectively by the inhibition of caspase activities. So, we ascertained STS carried out the inhibition of apoptosis by targeting other pathway. Meanwhile, E-64d inhibits autophagy and promotes apoptosis. This means autophagy is a cytoprotective mechanism, and the inhibition of autophagy promotes the development of apoptosis. However, E-64 can not impact the development of apoptosis. We conjectured that may be due to the poor membrane permeability of E-64. These results demonstrate STS regulate other unknown target rather then caspase to inhibit apoptosis induced by serum deprivation. In order to determine whether inhibition of STS on caspase can regulate apoptosis, cisplatin-induced caspase-dependent apoptosis was tested. The results showed that STS could not inhibit caspase-dependent apoptosis, but zVAD-fmk as a positive control effectively inhibited caspase-dependent apoptosis. These results documented that the inhibition of caspase by STS is insufficient to inhibit caspase-dependent apoptosis.
It was reported lysosomal membrane permeability (LMP) was shown to be involved in cell autophagy and apoptosis. Therefore, our experiment also examined changes of LMP. After serum deprivation, the increase of LMP was detected, and STS can decrease the level of increased LMP. However, neither cysteine proteinase inhibitors (E-64 and E-64d) nor caspase inhibitor (zVAD-fmk) can inhibit increased LMP. So we can determine the change of LMP is not related to cysteine proteinase activities. Meanwhile, the inhibition of autophagy by E-64d could not decrease LMP, this mean LMP is the upstream of autophagy or there was not relationship between LMP and autophagy. Increasing evidences indicate LMP can regulate caspase-dependent and caspase-independent apoptosis, we presumed STS inhibited the increase of LMP to inhibit caspase-independent apoptosis.
In addition, in our experiment, the degradation of poly ADP-ribose polymerase (PARP) was detected to determent the activity of caspase-3. However, we surprisedly detected there are considerable degradation of PARP notwithstanding the apoptosis induced by serum deprivation is a caspase independent apoptosis, and STS could inhibit effectively the degradation of PARP. According to recent researches, many cysteine proteases degraded PARP to different molecular weight. So, we presumed STS inhibit the degradation of PARP by the inhibition of cysteine protease.
We also detected the ability of asparagines which inhibit autophagic-lysosomal delivery serum deprivation induced apoptosis and autophagy on autophagy and apoptosis induced by serum deprivation. Asparagine can inhibit LMP and apoptosis, but this result contrary to the effect of E-64d on serum deprivation induced apoptosis. Autophagy is generally considered to be a cellular protective mechanism, so we presumed that large concentration of STS (10mM) could target to other unknown pathway to regulate apoptosis.
In summary, the serum deprivation-induced apoptosis is a caspase independent apoptosis with autophagy, and the inhibition of autophagy promotes apoptosis. The inhibition of autophagy by STS is through the regulation of cysteine proteases activities. Meanwhile, we presumed the inhibition of apoptosis is through the regulation of LMP.
In addition to the regulation of apoptosis and autophagy, cathepsin is also involved in the development of tumor cells. It is reported that cathepsins promote tumor cell migration and invasion through the degradation of extracellular matrix components and adhesion-related proteins. Yoko Hashimoto and his colleagues demonstrate that approximately 10-fold higher mature cathepsin L activity was secreted in a medium of human fibrosarcoma (HT 1080) cells, compared with their intracellular activity and speculate that the cathepsin L found in HT1080 cell medium is involved in cancer invasion and metastasis. Therefore, we have investigated the inhibitory effect of STS and E-64 on HT1080 cell migration and invasion. The results showed that STS and E-64 could inhibit HT1080 cell migration and invasion effectively.
Further more, matrix metalloproteinase (MMP) is chosen as target for inhibitor screening. Traditional Chinese medicine (TCM) has a significant effect in the treatment of cancer, but the mechanism is not clear. We wonder to know whether TCM can inhibit MMP activity to treat cancer. So we screened MMP inhibitor from TCM. Stir-baked Fructus Gardeniae, Polygoni Multiflori Gaulis, and Ramulus Cinnamomi can inhibit MMP activity in vitro and regulate the cell behavior in vivo. Our findings will help to understand the mechanism of these TCM.
引文
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