肿瘤发生及治疗过程中p53蛋白线粒体迁移及相关细胞凋亡途径的研究
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摘要
p53蛋白作为一种重要的肿瘤抑制因子,在细胞或病毒性致癌基因(Oncogene)被表达的时候会被自动激活并启动细胞凋亡途径杀死突变细胞,是生物体对抗癌变的主要机制。p53蛋白在被外界条件激活后,通过转录途径(transcriptional-dependent pathway)和非转录途径(transcriptional-independent pathway)共同诱导细胞凋亡的发生。p53蛋白的非转录活性主要来自于线粒体内的p53蛋白。虽然目前对线粒体p53蛋白功能方面仍有很多争议,但p53蛋白在激活后的线粒体迁移(p53 mitochondrial translocation)已经有大量数据支持并被人们所接受了。尽管如此,目前关于p53线粒体迁移机制方面的认识还很少,且存在很多争议性的观点。本文工作的重点就是研究肿瘤发生过程中以及癌症细胞中的p53蛋白线粒体迁移机制,详细考察了线粒体生理功能对皮肤肿瘤发生过程(skin carcinogenesis)中p53蛋白线粒体迁移的影响,并研究了突变p53蛋白在淋巴瘤细胞(lymphoma cells)中的线粒体迁移状况以及相关的凋亡功能。本文首次揭示了线粒体渗透性转换(mitochondrial permeability transition)以及线粒体解偶联效应(mitochondrial uncoupling effect)对p53蛋白线粒体迁移的调控作用,证明了突变p53蛋白线粒体迁移在癌症细胞中的存在及潜在的凋亡诱导能力,这些实验结果有助于更好的理解p53蛋白的线粒体迁移机制以及p53非转录凋亡途径,同时也为进一步设计以线粒体p53为靶标的癌症预防与治疗手段提供理论基础。
The tumor suppresser p53 is known to trigger apoptosis in response to DNA damage, oncogene activation, or certain chemotherapeutic drugs. Potentially, as a defending mechanism against carcinogenesis, p53 induces apoptosis via transcriptional-dependent and transcriptional-independent pathways, two fundamentally different, but synergistic mechanisms of action. In addition to its transcriptional activation, it has been shown that a fraction of p53 translocates into mitochondria at the very early stage of apoptosis which, in several conditions, is necessary for the activation of p53-apoptosis network. However, the mitochondrial events that affect p53 translocation and associated apoptosis are still unclear.
Herein, we studied whether p53 mitochondrial translocation and subsequent apoptosis were affected by mitochondrial functional alternation including mitochondrial uncoupling and blocking permeability transition pore during skin tumor promotion. Our studies revealed several interesting facts: (1) TPA induced p53 mitochondrial translocation and associated mitochondrial dysfunction and apoptosis in JB6 P+ cells. (2) Mitochondrial uncoupling and blocking permeability transition pore both suppressed TPA-induced p53 mitochondrial translocation in JB6 P+ cells. (3) Mitochondrial uncoupling and blocking permeability transition pore both prevented mitochondrial dysfunction and apoptosis associated with p53 mitochondrial translocation in JB6 P+ cells. (4) Blocking permeability transition pore reduced the mitochondrial p53 level in DBA2/J mouse skin epidermal tissues after DMBA/TPA treatment. (5) UCP2-knockdown JB6 P+ cells showed enhanced p53 mitochondrial translocation and decreased colony formation in response to TPA treatment.
All these results suggested that mitochondrial functional alternation including mitochondrial uncoupling and permeability transition could modulate p53 mitochondrial translocation and further affect downstream mitochondrial dysfunction and apoptosis pathway during early skin tumor promotion. More over, these effects existed both in vivo and in vitro, and were important for the tumor formation process.
The above mentioned p53 apoptotic activities belong to wt p53 and have been well documented for years. Nevertheless, as a pivotal tumor suppresser, p53 is the most commonly mutated gene in human cancers. Accumulated studies reveal that more than 50% of human cancers contain mutations in p53 gene. These mutations strongly select for p53 proteins that fail to bind to DNA in a sequence-specific fashion and thus block its transcriptional activities. However, the DNA binding activity is not necessary for p53 to exert its transcriptional-independent activities and a number of studies have suggested mitochondrial localization of mutant p53 in cancer cells. These results indicate a potential role of mutant p53 in the mitochondria of cancer cells. Since our above results have revealed a potential relationship between mitochondrial metabolism status and p53 mitochondrial translocation, we chose several lymphoma cell line with different p53 status (wt, mutant, or null) to further investigated whether mutant p53 translocates into mitochondria during cancer therapy, whether mutant p53 affects mitochondrial functions including complex activities and apoptosis, and whether restoring mutant p53 by ellipticine enforces mutant p53 to affect mitochondrial functions.. Our results showed that: (1) The expression levels of both wt and mutant p53 were increased in lymphoma cells upon doxorubicin treatment. (2) Both wt and mutant p53 translocated into mitochondria upon doxorubicin treatment. (3) Mutant p53-bearing DHL-4 cells were more resistant to doxorubicin treatment than wt p53-containing DoHH2 cells. (4) Decreases in mitochondrial Complex I and Complex II activities were associated with translocation of wt but not mutant p53. (5) A small molecule, ellipticine, restored the activity of mutant p53 which further affect mitochondrial function and apoptosis.
These results from lymphoma cells demonstrated that during cancer therapy, both wt and mutant p53 could translocate into mitochondria while only wt p53 mitochondrial translocation could further induce mitochondrial dysfunction and apoptosis. This means, in addition to the blocking effect on transcriptional-dependent pathway, mutations in p53 can also block the transcriptional-independent pathway, and very interestingly, status of p53 doesn’t affect its mitochondrial translocation. Even though the mechanism this phenomenon is still unclear, these blocking effect might result from conformational alternation caused by mutation, since a small molecule, ellipticine, can interact with mutant p53 and restore its apoptotic activity in response to doxorubicin treatment.
Taken together, our studies provide a deep insight into the mechanism of p53 mitochondrial translocation and associated alternation in apoptotic network. Our studies concerned both cancer cells and normal epithermal cells during early tumor promotion. Our results and conclusions may provide novel information regarding the role of p53 transcriptional-independent pathway in carcinogenesis, which may contribute to the understanding of the relationship between p53 status and cancer chemoresistance from a new angle, helping to design a better strategy for p53-mediated therapy.
The tumor suppresser p53 is known to trigger apoptosis in response to DNA damage, oncogene activation, or certain chemotherapeutic drugs. Potentially, as a defending mechanism against carcinogenesis, p53 induces apoptosis via transcriptional-dependent and transcriptional-independent pathways, two fundamentally different, but synergistic mechanisms of action. In addition to its transcriptional activation, it has been shown that a fraction of p53 translocates into mitochondria at the very early stage of apoptosis which, in several conditions, is necessary for the activation of p53-apoptosis network. However, the mitochondrial events that affect p53 translocation and associated apoptosis are still unclear.
Herein, we studied whether p53 mitochondrial translocation and subsequent apoptosis were affected by mitochondrial functional alternation including mitochondrial uncoupling and blocking permeability transition pore during skin tumor promotion. Our studies revealed several interesting facts: (1) TPA induced p53 mitochondrial translocation and associated mitochondrial dysfunction and apoptosis in JB6 P+ cells. (2) Mitochondrial uncoupling and blocking permeability transition pore both suppressed TPA-induced p53 mitochondrial translocation in JB6 P+ cells. (3) Mitochondrial uncoupling and blocking permeability transition pore both prevented mitochondrial dysfunction and apoptosis associated with p53 mitochondrial translocation in JB6 P+ cells. (4) Blocking permeability transition pore reduced the mitochondrial p53 level in DBA2/J mouse skin epidermal tissues after DMBA/TPA treatment. (5) UCP2-knockdown JB6 P+ cells showed enhanced p53 mitochondrial translocation and decreased colony formation in response to TPA treatment.
All these results suggested that mitochondrial functional alternation including mitochondrial uncoupling and permeability transition could modulate p53 mitochondrial translocation and further affect downstream mitochondrial dysfunction and apoptosis pathway during early skin tumor promotion. More over, these effects existed both in vivo and in vitro, and were important for the tumor formation process.
The above mentioned p53 apoptotic activities belong to wt p53 and have been well documented for years. Nevertheless, as a pivotal tumor suppresser, p53 is the most commonly mutated gene in human cancers. Accumulated studies reveal that more than 50% of human cancers contain mutations in p53 gene. These mutations strongly select for p53 proteins that fail to bind to DNA in a sequence-specific fashion and thus block its transcriptional activities. However, the DNA binding activity is not necessary for p53 to exert its transcriptional-independent activities and a number of studies have suggested mitochondrial localization of mutant p53 in cancer cells. These results indicate a potential role of mutant p53 in the mitochondria of cancer cells. Since our above results have revealed a potential relationship between mitochondrial metabolism status and p53 mitochondrial translocation, we chose several lymphoma cell line with different p53 status (wt, mutant, or null) to further investigated whether mutant p53 translocates into mitochondria during cancer therapy, whether mutant p53 affects mitochondrial functions including complex activities and apoptosis, and whether restoring mutant p53 by ellipticine enforces mutant p53 to affect mitochondrial functions.. Our results showed that: (1) The expression levels of both wt and mutant p53 were increased in lymphoma cells upon doxorubicin treatment. (2) Both wt and mutant p53 translocated into mitochondria upon doxorubicin treatment. (3) Mutant p53-bearing DHL-4 cells were more resistant to doxorubicin treatment than wt p53-containing DoHH2 cells. (4) Decreases in mitochondrial Complex I and Complex II activities were associated with translocation of wt but not mutant p53. (5) A small molecule, ellipticine, restored the activity of mutant p53 which further affect mitochondrial function and apoptosis.
These results from lymphoma cells demonstrated that during cancer therapy, both wt and mutant p53 could translocate into mitochondria while only wt p53 mitochondrial translocation could further induce mitochondrial dysfunction and apoptosis. This means, in addition to the blocking effect on transcriptional-dependent pathway, mutations in p53 can also block the transcriptional-independent pathway, and very interestingly, status of p53 doesn’t affect its mitochondrial translocation. Even though the mechanism this phenomenon is still unclear, these blocking effect might result from conformational alternation caused by mutation, since a small molecule, ellipticine, can interact with mutant p53 and restore its apoptotic activity in response to doxorubicin treatment.
Taken together, our studies provide a deep insight into the mechanism of p53 mitochondrial translocation and associated alternation in apoptotic network. Our studies concerned both cancer cells and normal epithermal cells during early tumor promotion. Our results and conclusions may provide novel information regarding the role of p53 transcriptional-independent pathway in carcinogenesis, which may contribute to the understanding of the relationship between p53 status and cancer chemoresistance from a new angle, helping to design a better strategy for p53-mediated therapy.
引文
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