土槿皮乙酸诱导小鼠真皮成纤维L929细胞有丝分裂灾变及衰老作用机制研究
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摘要
土槿皮乙酸(Pseudolaric acid B, PAB)是由松科植物金钱松(Pseudolarix Kaempferi Gorden)的干燥根皮或近根树皮提取出的新型二萜酸化合物。现代药理研究表明,土槿皮乙酸具有抗真菌、抗微管、抗肿瘤、抗血管生成、抗生育等多种药理作用,目前土槿皮乙酸已做为抗真菌药物被广泛使用。微管是抗癌药物的重要靶点,以往对土槿皮乙酸的研究表明土槿皮乙酸是一种新型的微管抑制剂,而微管蛋白则是抗肿瘤重要靶点之一,因此土槿皮乙酸有望成为抗肿瘤药物。初步研究结果还发现土槿皮乙酸具有明显的体内外抗肿瘤活性,而且在有效剂量范围内对小鼠骨髓、肝、肾等毒性低。之前的研究发现土槿皮乙酸可通过诱导周期阻滞、凋亡等过程抑制多种肿瘤细胞的增殖。本研究选用小鼠纤维肉瘤L929细胞作为研究对象,考察土槿皮乙酸诱导肿瘤细胞发生有丝分裂灾变、衰老、自噬等程序性死亡过程分子机制,进一步为土槿皮乙酸成为抗肿瘤药物提供理论依据。
本研究中,形态学观察结果显示土槿皮乙酸作用L929细胞后,随着给药时间的延长,细胞变圆、变大、变扁平、紧密贴壁。土槿皮乙酸通过抑制微管聚合,破坏微管束状结构、改变细胞骨架、影响纺锤体功能,引起有丝分裂异常。流式细胞术周期分析显示土槿皮乙酸诱导L929细胞出现G2/M期周期阻滞。p-Histone(p-H3)在M期中表达量最高,可以作为M期的标志蛋白。p-H3蛋白水平变化过程和有丝分裂指数分析结果进一步表明土槿皮乙酸诱导L929细胞出现M期阻滞,而非G2期阻滞。进一步研究发现阻滞于M期的细胞因为cyclinBl-cdc2复合物活力的降低发生纺锤体检查点适应,跳出M期进入下一个分裂周期,形成多核细胞。给药时间大于3天后,一部分多核细胞通过凋亡途径死亡。我们还选用了小鼠真皮纤维细胞和人结肠癌HCT116细胞验证了土槿皮乙酸在L929细胞中出现的有丝分裂灾变是否具有普遍性,结果表明土槿皮乙酸诱导肿瘤细胞发生有丝分裂灾变这一现象并非普遍性,而是细胞特异性。
上述结果表明土槿皮乙酸诱导L929细胞出现细胞变大、变扁平、紧密贴壁、多核化等衰老细胞的特点。因此,进一步考察有丝分裂灾变细胞的去向显得尤为重要。结果表明药物作用3天后小部分有丝分裂灾变细胞发生凋亡,大部分有丝分裂灾变细胞进入衰老状态。免疫蛋白印迹结果显示土槿皮乙酸通过p19-p53-p21p16-Rb通路诱导L929细胞衰老。研究结果还表明土槿皮乙酸诱导L929细胞产生自噬。进一步研究显示自噬抑制剂3MA和氯喹均能推迟土槿皮乙酸诱导的衰老进程,表明自噬促进衰老过程,其后我们还采用Atg5特异性siRNA验证了该结果。此外,流式细胞术结果显示土槿皮乙酸作用L929细胞后线粒体功能严重受损,包括：细胞胞浆内大量活性氧蓄积,线粒体内超氧阴离子水平增加、线粒体数目增加、呼吸链损伤线粒体比率增加、线粒体ATP生成能力降低。接下来,我们发现土槿皮乙酸在L929细胞中诱导的自噬和活性氧/线粒体损伤相互影响,形成一个正反馈通路,正是该正反馈回路促进衰老的进程。最后,为了检测土槿皮乙酸诱导的衰老细胞可以生存多长时间,延长药物作用时间直至6天,观察形态学变化和周期变化。结果显示土槿皮乙酸作用5天后细胞体积缩小,出现碎片细胞,提示土槿皮乙酸诱导L929细胞形成的衰老细胞持续一定时间后最终走向死亡。
另外,本研究中还考察了mTOR在土槿皮乙酸诱导L929细胞死亡过程中的作用。研究结果表明AKT/mTOR通路的失活参与土槿皮乙酸诱导的自噬,而且P53、JNK、ROS三者之间互相促进,形成一个正反馈调节通路。进一步研究表明ROS-JNK-p53通路通过抑制mTOR的活力调控自噬,促进衰老进程。胰岛素、雷帕霉素和TSC2特异性siRNA预处理等方法进一步验证mTOR的失活在土槿皮乙酸诱导L929细胞衰老过程中的作用。此外,我们还选用了MCF-7细胞验证mTOR的失活在土槿皮乙酸诱导的衰老过程中的作用是否具有普遍性。结果表明mTOR的失活也参与土槿皮乙酸诱导的MCF-7细胞衰老过程。
Pseudolaric acid B (PAB), the primary biologically active compound isolated from the root bark of P. kaempferi Gordon. Previous studies demonstrated that PAB exhibited multiple pharmacological effects including antifungal, antimicrotubule, antibiosis and antitumor. It is reported that PAB is a novel microtubule-destabilizing agent that exhibits antitumor activity in vivo and in vitro. In addition, PAB shows no obvious toxicities to the liver and kidney. PAB exhibits anti-tumor effect in vitro primarily via cell cycle arrest and apoptosis. In this study, we chose L929cells to study the mechanisms of mitotic catastrophe, senescence, autophagy and ROS generation.
PAB induced mitotic catastrophe in L929cells. The cells became flat, enlarged and adherent after treated with PAB by72h. PAB interfered with the function of the mitotic spindle apparatus by inhibiting microtubule polymerization, resulting in G2/M phase arrest. The level of histone H3phosphorylation, a specific mitotic marker, increased up to24h after treatment and then decreased in a time-dependent manner. In addition, the mitotic index increased during a24h treatment with PAB, suggesting that PAB arrested cell cycle progression at mitosis. The M phase arrested cells undergone mitotic slippage due to the inactivation of the cylinBl-cdc2complex, resulting in multinucleated cells. To investigate whether the mitotic slippage and subsequent apoptosis observed was specific for the L929cell line or the species, the effects of PAB on primary mouse dermal fibroblast cells and colorectal carcinoma HCT-116cells were examined. The results indicated that the mitotic slippage and subsequent apoptosis induced by PAB was not common but instead was specific for L929cells.
Besides apoptosis, a majority of the cells undergoing mitotic catastrophe entered a period of senescence. PAB induced senescence through p19-p53-p21and p16-Rb pathways in L929cells. Autophagy inhibitors (3-Methyladenine (3MA), chloroquine (CQ) or ATG5siRNA significantly delayed the senescence process, indicating that autophagy facilitated senescence. Further data indicated that PAB triggered serious mitochondrial dysfunction including reactive oxygen species (ROS) generation, the increase in mitochondrial mass, damage to the respiratory chain and ATP production. Moreover, ROS scavenger significantly decreased the autophagic level and improved mitochondrial function. Additionally, autophagy inhibitors effectively reduced ROS levels and ameliorated mitochondrial function, In conclusion, autophagy promoted senescence via enhancement of ROS generation and mitochondrial dysfunction in PAB-treated L929cells. We also investigated the fate of the senescent cells. The results showed that the cells were not stationary senescent, on the contrary, the ratio of dead cells significantly increased after a5-7days exposure of PAB.
PAB was also found to trigger autophagy via inhibiting Akt/mTOR activity in L929cells, In addition, autophagy was demonstrated to reinforce senescence through regulating the senescence pathways. Thus, we focused on the detailed molecular mechanisms whereby autophagy promoted senescence. PAB triggered a ROS-JNK-p53positive feedback loop played a crucial role in autophagy via repressing the activation of mTOR in L929cells. Furthermore, ROS-JNK-p53positive feedback loop was demonstrated to regulate senescence. TSC1/TSC2heterodimer, a downstream target of growth factor-phosphoinositide3-kinase-Akt signaling, negatively regulates mTOR activity. Activation of mTOR by insulin or inhibition of endogenous TSC2levels by siRNA obviously delayed PAB-induced senescence, In conclusion, mTOR inactivation by ROS-JNK-p53pathway played an important role in autophagy-dependent senescence in PAB-treated L929cells. Finally, mTOR inactivation was also demonstrated to be involved in autophagy-dependent senescence in PAB-treated MCF-7cells.
本研究中,形态学观察结果显示土槿皮乙酸作用L929细胞后,随着给药时间的延长,细胞变圆、变大、变扁平、紧密贴壁。土槿皮乙酸通过抑制微管聚合,破坏微管束状结构、改变细胞骨架、影响纺锤体功能,引起有丝分裂异常。流式细胞术周期分析显示土槿皮乙酸诱导L929细胞出现G2/M期周期阻滞。p-Histone(p-H3)在M期中表达量最高,可以作为M期的标志蛋白。p-H3蛋白水平变化过程和有丝分裂指数分析结果进一步表明土槿皮乙酸诱导L929细胞出现M期阻滞,而非G2期阻滞。进一步研究发现阻滞于M期的细胞因为cyclinBl-cdc2复合物活力的降低发生纺锤体检查点适应,跳出M期进入下一个分裂周期,形成多核细胞。给药时间大于3天后,一部分多核细胞通过凋亡途径死亡。我们还选用了小鼠真皮纤维细胞和人结肠癌HCT116细胞验证了土槿皮乙酸在L929细胞中出现的有丝分裂灾变是否具有普遍性,结果表明土槿皮乙酸诱导肿瘤细胞发生有丝分裂灾变这一现象并非普遍性,而是细胞特异性。
上述结果表明土槿皮乙酸诱导L929细胞出现细胞变大、变扁平、紧密贴壁、多核化等衰老细胞的特点。因此,进一步考察有丝分裂灾变细胞的去向显得尤为重要。结果表明药物作用3天后小部分有丝分裂灾变细胞发生凋亡,大部分有丝分裂灾变细胞进入衰老状态。免疫蛋白印迹结果显示土槿皮乙酸通过p19-p53-p21p16-Rb通路诱导L929细胞衰老。研究结果还表明土槿皮乙酸诱导L929细胞产生自噬。进一步研究显示自噬抑制剂3MA和氯喹均能推迟土槿皮乙酸诱导的衰老进程,表明自噬促进衰老过程,其后我们还采用Atg5特异性siRNA验证了该结果。此外,流式细胞术结果显示土槿皮乙酸作用L929细胞后线粒体功能严重受损,包括：细胞胞浆内大量活性氧蓄积,线粒体内超氧阴离子水平增加、线粒体数目增加、呼吸链损伤线粒体比率增加、线粒体ATP生成能力降低。接下来,我们发现土槿皮乙酸在L929细胞中诱导的自噬和活性氧/线粒体损伤相互影响,形成一个正反馈通路,正是该正反馈回路促进衰老的进程。最后,为了检测土槿皮乙酸诱导的衰老细胞可以生存多长时间,延长药物作用时间直至6天,观察形态学变化和周期变化。结果显示土槿皮乙酸作用5天后细胞体积缩小,出现碎片细胞,提示土槿皮乙酸诱导L929细胞形成的衰老细胞持续一定时间后最终走向死亡。
另外,本研究中还考察了mTOR在土槿皮乙酸诱导L929细胞死亡过程中的作用。研究结果表明AKT/mTOR通路的失活参与土槿皮乙酸诱导的自噬,而且P53、JNK、ROS三者之间互相促进,形成一个正反馈调节通路。进一步研究表明ROS-JNK-p53通路通过抑制mTOR的活力调控自噬,促进衰老进程。胰岛素、雷帕霉素和TSC2特异性siRNA预处理等方法进一步验证mTOR的失活在土槿皮乙酸诱导L929细胞衰老过程中的作用。此外,我们还选用了MCF-7细胞验证mTOR的失活在土槿皮乙酸诱导的衰老过程中的作用是否具有普遍性。结果表明mTOR的失活也参与土槿皮乙酸诱导的MCF-7细胞衰老过程。
Pseudolaric acid B (PAB), the primary biologically active compound isolated from the root bark of P. kaempferi Gordon. Previous studies demonstrated that PAB exhibited multiple pharmacological effects including antifungal, antimicrotubule, antibiosis and antitumor. It is reported that PAB is a novel microtubule-destabilizing agent that exhibits antitumor activity in vivo and in vitro. In addition, PAB shows no obvious toxicities to the liver and kidney. PAB exhibits anti-tumor effect in vitro primarily via cell cycle arrest and apoptosis. In this study, we chose L929cells to study the mechanisms of mitotic catastrophe, senescence, autophagy and ROS generation.
PAB induced mitotic catastrophe in L929cells. The cells became flat, enlarged and adherent after treated with PAB by72h. PAB interfered with the function of the mitotic spindle apparatus by inhibiting microtubule polymerization, resulting in G2/M phase arrest. The level of histone H3phosphorylation, a specific mitotic marker, increased up to24h after treatment and then decreased in a time-dependent manner. In addition, the mitotic index increased during a24h treatment with PAB, suggesting that PAB arrested cell cycle progression at mitosis. The M phase arrested cells undergone mitotic slippage due to the inactivation of the cylinBl-cdc2complex, resulting in multinucleated cells. To investigate whether the mitotic slippage and subsequent apoptosis observed was specific for the L929cell line or the species, the effects of PAB on primary mouse dermal fibroblast cells and colorectal carcinoma HCT-116cells were examined. The results indicated that the mitotic slippage and subsequent apoptosis induced by PAB was not common but instead was specific for L929cells.
Besides apoptosis, a majority of the cells undergoing mitotic catastrophe entered a period of senescence. PAB induced senescence through p19-p53-p21and p16-Rb pathways in L929cells. Autophagy inhibitors (3-Methyladenine (3MA), chloroquine (CQ) or ATG5siRNA significantly delayed the senescence process, indicating that autophagy facilitated senescence. Further data indicated that PAB triggered serious mitochondrial dysfunction including reactive oxygen species (ROS) generation, the increase in mitochondrial mass, damage to the respiratory chain and ATP production. Moreover, ROS scavenger significantly decreased the autophagic level and improved mitochondrial function. Additionally, autophagy inhibitors effectively reduced ROS levels and ameliorated mitochondrial function, In conclusion, autophagy promoted senescence via enhancement of ROS generation and mitochondrial dysfunction in PAB-treated L929cells. We also investigated the fate of the senescent cells. The results showed that the cells were not stationary senescent, on the contrary, the ratio of dead cells significantly increased after a5-7days exposure of PAB.
PAB was also found to trigger autophagy via inhibiting Akt/mTOR activity in L929cells, In addition, autophagy was demonstrated to reinforce senescence through regulating the senescence pathways. Thus, we focused on the detailed molecular mechanisms whereby autophagy promoted senescence. PAB triggered a ROS-JNK-p53positive feedback loop played a crucial role in autophagy via repressing the activation of mTOR in L929cells. Furthermore, ROS-JNK-p53positive feedback loop was demonstrated to regulate senescence. TSC1/TSC2heterodimer, a downstream target of growth factor-phosphoinositide3-kinase-Akt signaling, negatively regulates mTOR activity. Activation of mTOR by insulin or inhibition of endogenous TSC2levels by siRNA obviously delayed PAB-induced senescence, In conclusion, mTOR inactivation by ROS-JNK-p53pathway played an important role in autophagy-dependent senescence in PAB-treated L929cells. Finally, mTOR inactivation was also demonstrated to be involved in autophagy-dependent senescence in PAB-treated MCF-7cells.
引文
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