Labrecque S, Matlashewski G J
Institute of Parasitology, McGill University, Quebec, Canada.
Oncogene. 1995 Jul 20;11(2):387-92.
One of the mechanisms in which anticancer therapies function is to induce cell death by apoptosis. In this regard, the biological activity of p53 may be critical since the presence of p53 appears to play a role in apoptosis following genotoxic stress. In experimental systems using in vitro transformed primary cells, there is a direct correlation between the presence of p53 and apoptosis. For example, E1A/ras-transformed primary mouse fibroblasts are less viable and undergo apoptosis following genotoxic stress if these cells contain a wild type p53. In comparison, similarly transformed cells which are p53-deficient are more viable and will not undergo apoptosis under these conditions. Although these are important observations, it remains to be established whether there exists a similar relationship between the presence of wild type p53 and loss of cell viability following therapy in human tumour cells. One way to address this question is to target wild type p53 in human tumour cells using human papillomavirus E6 which mediates the degradation of wild type p53 through the ubiquitin pathway. In this manner, E6 engineered p53-deficient and parental p53-containing human tumour cells provides an appropriate experimental system in which to determine whether wild type p53 in tumour cells has influence on cell viability following genotoxic anticancer treatments. In the present study, the wild type p53 protein in human fibrosarcoma HT1080 cells were targeted with HPV-18 E6 and the viability of these cells in response to treatment with adriamycin, u.v.-irradiation and gamma-irradiation was examined. Data is presented which shows that p53-containing and p53-deficient cells were equally sensitive to these treatments. These data argue that the wild type p53 in these tumour cells does not cause these cells to be less viable when treated with anticancer agents or u.v.-irradiation. Therefore, the status of p53 alone in tumour cells may not be an indicator of response to anticancer treatments.
抗癌疗法发挥作用的机制之一是通过凋亡诱导细胞死亡。在这方面，p53的生物学活性可能至关重要，因为p53的存在似乎在基因毒性应激后的凋亡中发挥作用。在使用体外转化原代细胞的实验系统中，p53的存在与凋亡之间存在直接关联。例如，如果E1A/ras转化的原代小鼠成纤维细胞含有野生型p53，那么在基因毒性应激后它们的活力较低并会发生凋亡。相比之下，同样转化的p53缺陷型细胞更具活力，在这些条件下不会发生凋亡。尽管这些是重要的观察结果，但野生型p53的存在与人类肿瘤细胞治疗后细胞活力丧失之间是否存在类似关系仍有待确定。解决这个问题的一种方法是使用人乳头瘤病毒E6靶向人类肿瘤细胞中的野生型p53，E6通过泛素途径介导野生型p53的降解。通过这种方式，E6改造的p53缺陷型和含亲本p53的人类肿瘤细胞提供了一个合适的实验系统，用于确定肿瘤细胞中的野生型p53在基因毒性抗癌治疗后是否对细胞活力有影响。在本研究中，用HPV-18 E6靶向人纤维肉瘤HT1080细胞中的野生型p53蛋白，并检测这些细胞对阿霉素、紫外线照射和γ射线照射的反应后的活力。所呈现的数据表明，含p53和p53缺陷的细胞对这些治疗同样敏感。这些数据表明，在用抗癌药物或紫外线照射处理时，这些肿瘤细胞中的野生型p53不会导致这些细胞活力降低。因此，肿瘤细胞中单独的p53状态可能不是对抗癌治疗反应的指标。
