ErbB_2及其结合蛋白Erbin在TRAIL介导的乳腺癌细胞凋亡中的作用及分子机制研究
摘要
TRAIL(tumor necrosis factor-related apoptosis-inducing ligand)是肿瘤坏死因子(TNF)超家族的一个新成员,能够特异地诱导多种肿瘤细胞凋亡而对大多数正常细胞没有毒性,因此备受人们的关注。然而研究发现,还有一些肿瘤细胞对TRAIL不敏感。本文利用对TRAIL敏感性不同的乳腺癌MCF-7和MDA-MB-231细胞株来研究肿瘤细胞对TRAIL敏感性不同的分子机制。
本研究发现,在TRAIL不敏感的MCF-7细胞中,rsTRAIL不能引起ErbB_2和Erbin表达变化,PKCδ抑制剂rottlerin单独或与rsTRAIL联合处理都可以导致ErbB_2和Erbin表达下调,同时抑制了ErbB_2下游的AKT信号通路的活化。而在敏感的MDA-MB-231细胞中,rsTRAIL单独处理就可以引起ErbB_2表达下调,对Erbin表达没有影响。进一步研究发现,caspase-8抑制剂Z-IETD-FMK能够抑制MCF-7细胞中rottlerin与rsTRAIL引起的ErbB_2表达下调以及MDA-MB-231细胞中rsTRAIL引起的ErbB_2的表达下调,而对Erbin的表达变化没有影响,说明caspase-8能够下调ErbB_2的表达。MDA-MB-231细胞中,rsTRAIL可以抑制NF-κB的活性;在MCF-7细胞中,rsTRAIL却可以激活NF-κB,提示在敏感的MDA-MB-231细胞中,由于rsTRAIL抑制了NF-κB和ErbB_2这两条和增殖密切相关的信号通路,使细胞在增殖和凋亡的动态平衡中走向凋亡;而在不敏感的MCF-7细胞中,由于PKCδ的高活性和rsTRAIL对NF-κB的激活,使细胞对TRAIL不敏感,在rottlerin和rsTRAIL的协同作用下,抑制了增殖信号通路,增加了对TRAIL的敏感性。
使用RNA干扰技术抑制Erbin表达,ErbB_2的表达也降低,并导致ErbB_2的泛素化增加;同时,MCF-7细胞对TRAIL的敏感性增加,细胞内NF-κB的活性也受到抑制。表明Erbin作为ErbB_2的结合蛋白,可抑制ErbB_2的泛素化而维持其稳定性,并导致ErbB_2在乳腺癌细胞中高表达,这可能是MCF-7细胞对TRAIL不敏感的原因之一。
本研究首次报道了Erbin和ErbB_2的相互作用机制,为我们深入探讨TRAIL诱导肿瘤细胞凋亡的作用机制及其耐药性的问题提供了新的思路。
Tumor necrosis factor(TNF)-related apoptosis-inducing ligand(TRAIL) is a member of the TNF superfamily with the ability to selectively induce apoptosis in a wide variety of transformed cell lines of diverse origin,but not in the most of normal cells. However,some cancer cell lines are resistant to TRAIL cytotoxicity.In this study, two breast cancer cell lines(MDA-MB-231 and MCF-7) were used to examine the molecular mechanism of different sensitivity to rsTRAIL.Erbin is a new member of LAP family,with 16 LRRs and one PDZ domain,firstly identified as a binding partner for ErbB_2.Via its domains,Erbin could bind many proteins in cytoplasm. More and more studies indicate that Erbin plays an important role not only in receptor localization or cell signaling but also in the establishment and the maintenance of cell to cell and cell to basement membrane adhesion.Therefore,further studies on the role of Erbin in cell signal transduction,especially its interaction with ErbB_2,is significant for comprehensive understanding of carcinogenesis and apoptosis-based cancer therapy.
We showed in the present study that the expression of ErbB_2 and Erbin were not changed in MCF-7 cells treated with TRAIL,which is not sensitive to TRAIL cytotoxicity,while PKCδinhibitor,rottlerin,sensitized MCF-7 cells to TRAIL cyototoxicity and down-regulated the expression of both ErbB_2 and Erbin in the presence of TRAIL or not.However,the expression of ErbB_2 was down-regulated, but the expression of Erbin was not changed in MDA-MB-231 cells in the presence of TRAIL only,since the cells are sensitive to TRAIL cytotoxicity.Further study demonstrated that the down-regulation of ErbB_2,but not Erbin,was arrested by the inhibitor of caspase-8,Z-IETD-FMK,in both MCF-7 and MDA-MB-231 cells treated with TRAIL and/or rottlerin,suggesting that caspase-8 down-regulated the expression level of ErbB_2 induced by TRAIL.Downstream signal study showed that NF-κB activity was inhibited by rsTRAIL in MDA-MB-231 cells and enhanced in MCF-7 cells,suggesting that NF-κB activity might be a determine factor for cell apoptosis and proliferation.These data indicated that TRAIL inhibited the proliferation signal such as NF-κB and ErbB_2,and activated the apoptosis signals,so the balance trended to apoptosis in MDA-MB-231 cells,while high activity of PKCδand NF-κB in MCF-7 cells induced by rsTRAIL enabled the cells insensitive to TRAIL cytotoxicity, and therefore,the combination of rottlerin and rsTRAIL inhibited the proliferation signal pathway and induced cell apoptosis.
Furthermore,we demonstrated the suppression of Erbin expression by using RNAi technology facilitates the sensitivity of the cells to TRAIL,the expression of ErbB_2 was down-regulated,and ubiquitination of ErbB_2 was increased in the MCF-7 cells. Moreover,AKT signal pathway and NF-κB activation,downstream of ErbB_2,was also inhibited in the MCF-7 cells,in which the expression of Erbin was declined by siRNA technology,suggestiong that Erbin could sustain the stability of ErbB_2 by suppression ErbB_2 ubiquitination and it might be one of the reasons that MCF-7 cells are resistant to TRAIL cytotoxicity.
In summary,we have reported for the first time that Erbin could regulate ErbB_2 expression by suppressing ErbB_2 ubiquitination.These results are significant implication for understanding the resistant mechanism to TRAIL in MCF-7 cells and the mechanism of apoptosis-induced by TRAIL.
本研究发现,在TRAIL不敏感的MCF-7细胞中,rsTRAIL不能引起ErbB_2和Erbin表达变化,PKCδ抑制剂rottlerin单独或与rsTRAIL联合处理都可以导致ErbB_2和Erbin表达下调,同时抑制了ErbB_2下游的AKT信号通路的活化。而在敏感的MDA-MB-231细胞中,rsTRAIL单独处理就可以引起ErbB_2表达下调,对Erbin表达没有影响。进一步研究发现,caspase-8抑制剂Z-IETD-FMK能够抑制MCF-7细胞中rottlerin与rsTRAIL引起的ErbB_2表达下调以及MDA-MB-231细胞中rsTRAIL引起的ErbB_2的表达下调,而对Erbin的表达变化没有影响,说明caspase-8能够下调ErbB_2的表达。MDA-MB-231细胞中,rsTRAIL可以抑制NF-κB的活性;在MCF-7细胞中,rsTRAIL却可以激活NF-κB,提示在敏感的MDA-MB-231细胞中,由于rsTRAIL抑制了NF-κB和ErbB_2这两条和增殖密切相关的信号通路,使细胞在增殖和凋亡的动态平衡中走向凋亡;而在不敏感的MCF-7细胞中,由于PKCδ的高活性和rsTRAIL对NF-κB的激活,使细胞对TRAIL不敏感,在rottlerin和rsTRAIL的协同作用下,抑制了增殖信号通路,增加了对TRAIL的敏感性。
使用RNA干扰技术抑制Erbin表达,ErbB_2的表达也降低,并导致ErbB_2的泛素化增加;同时,MCF-7细胞对TRAIL的敏感性增加,细胞内NF-κB的活性也受到抑制。表明Erbin作为ErbB_2的结合蛋白,可抑制ErbB_2的泛素化而维持其稳定性,并导致ErbB_2在乳腺癌细胞中高表达,这可能是MCF-7细胞对TRAIL不敏感的原因之一。
本研究首次报道了Erbin和ErbB_2的相互作用机制,为我们深入探讨TRAIL诱导肿瘤细胞凋亡的作用机制及其耐药性的问题提供了新的思路。
Tumor necrosis factor(TNF)-related apoptosis-inducing ligand(TRAIL) is a member of the TNF superfamily with the ability to selectively induce apoptosis in a wide variety of transformed cell lines of diverse origin,but not in the most of normal cells. However,some cancer cell lines are resistant to TRAIL cytotoxicity.In this study, two breast cancer cell lines(MDA-MB-231 and MCF-7) were used to examine the molecular mechanism of different sensitivity to rsTRAIL.Erbin is a new member of LAP family,with 16 LRRs and one PDZ domain,firstly identified as a binding partner for ErbB_2.Via its domains,Erbin could bind many proteins in cytoplasm. More and more studies indicate that Erbin plays an important role not only in receptor localization or cell signaling but also in the establishment and the maintenance of cell to cell and cell to basement membrane adhesion.Therefore,further studies on the role of Erbin in cell signal transduction,especially its interaction with ErbB_2,is significant for comprehensive understanding of carcinogenesis and apoptosis-based cancer therapy.
We showed in the present study that the expression of ErbB_2 and Erbin were not changed in MCF-7 cells treated with TRAIL,which is not sensitive to TRAIL cytotoxicity,while PKCδinhibitor,rottlerin,sensitized MCF-7 cells to TRAIL cyototoxicity and down-regulated the expression of both ErbB_2 and Erbin in the presence of TRAIL or not.However,the expression of ErbB_2 was down-regulated, but the expression of Erbin was not changed in MDA-MB-231 cells in the presence of TRAIL only,since the cells are sensitive to TRAIL cytotoxicity.Further study demonstrated that the down-regulation of ErbB_2,but not Erbin,was arrested by the inhibitor of caspase-8,Z-IETD-FMK,in both MCF-7 and MDA-MB-231 cells treated with TRAIL and/or rottlerin,suggesting that caspase-8 down-regulated the expression level of ErbB_2 induced by TRAIL.Downstream signal study showed that NF-κB activity was inhibited by rsTRAIL in MDA-MB-231 cells and enhanced in MCF-7 cells,suggesting that NF-κB activity might be a determine factor for cell apoptosis and proliferation.These data indicated that TRAIL inhibited the proliferation signal such as NF-κB and ErbB_2,and activated the apoptosis signals,so the balance trended to apoptosis in MDA-MB-231 cells,while high activity of PKCδand NF-κB in MCF-7 cells induced by rsTRAIL enabled the cells insensitive to TRAIL cytotoxicity, and therefore,the combination of rottlerin and rsTRAIL inhibited the proliferation signal pathway and induced cell apoptosis.
Furthermore,we demonstrated the suppression of Erbin expression by using RNAi technology facilitates the sensitivity of the cells to TRAIL,the expression of ErbB_2 was down-regulated,and ubiquitination of ErbB_2 was increased in the MCF-7 cells. Moreover,AKT signal pathway and NF-κB activation,downstream of ErbB_2,was also inhibited in the MCF-7 cells,in which the expression of Erbin was declined by siRNA technology,suggestiong that Erbin could sustain the stability of ErbB_2 by suppression ErbB_2 ubiquitination and it might be one of the reasons that MCF-7 cells are resistant to TRAIL cytotoxicity.
In summary,we have reported for the first time that Erbin could regulate ErbB_2 expression by suppressing ErbB_2 ubiquitination.These results are significant implication for understanding the resistant mechanism to TRAIL in MCF-7 cells and the mechanism of apoptosis-induced by TRAIL.
引文
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