Antisense attenuation of p21 sensitizes kidney cancer to apoptosis in response to conventional DNA damaging chemotherapy associated with enhancement of phospho-p53.
Antisense attenuation of p21 sensitizes kidney cancer to apoptosis in response to conventional DNA damaging chemotherapy associated with enhancement of phospho-p53.
复制标题
p21 反义减弱使肾癌对细胞凋亡敏感，这是对与磷酸化 p53 增强相关的传统 DNA 损伤化疗的反应。
DOI：
10.1016/j.juro.2008.02.038
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Weiss,RobertH
中科院分区：
文献类型：
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作者：
Park,See-Hyoung;Park,Jin-Young;Weiss,RobertH
肾癌转移后对常规化疗有抵抗力，是众所周知的难治疾病。因此，转移性肾细胞癌患者的5年生存率低于10%，需要新的治疗方法。细胞周期蛋白激酶抑制剂p21通常通过DNA损伤响应性p53途径的诱导来传递抗凋亡功能。我们利用p21的这一功能，并使用反义的方法来敏感p53-wt肾细胞癌细胞化疗诱导的凋亡，通过衰减p21蛋白levels.Materials和MethodsThe人肾细胞癌细胞系ACHN和SN 12 C转染反义和控制寡核苷酸。p21和凋亡相关蛋白水平以及凋亡的评估使用标准techniques. ResultsAchN和SN 12 C细胞与硫代磷酸反义p21寡脱氧核苷酸的预孵育显著减弱p21并使细胞对阿霉素和顺铂诱导的凋亡敏感，使得在反义存在下可以使用数量级更少的多柔比星或顺铂以实现等同或更大的细胞死亡。此外，与p21衰减相关的ACHN细胞死亡机制涉及抗凋亡蛋白水平的降低以及促凋亡蛋白p53活性形式的增加。结论由于硫代磷酸反义寡核苷酸在肾脏和肝脏中的积累程度高于其他任何器官，我们的研究结果提示，在肾癌常规化疗联合反义p21寡核苷酸的重新评估。
PurposeKidney cancer is notoriously difficult to treat when metastatic due to its resistance to conventional chemotherapy. Thus, the 5-year survival rate in patients with metastatic renal cell carcinoma is less than 10% and novel approaches to treatment are needed. The cyclin kinase inhibitor p21 generally conveys an anti-apoptotic function through its induction by the DNA damage responsive p53 pathway. We capitalized on this function of p21 and used an antisense approach to sensitize p53-wt renal cell carcinoma cells to chemotherapy induced apoptosis by attenuating p21 protein levels.Materials and MethodsThe human renal cell carcinoma cell lines ACHN and SN12C were transfected with antisense and control oligodeoxynucleotides. Assessment of p21 and apoptosis relevant protein levels as well as apoptosis was performed using standard techniques.ResultsPre-incubation of ACHN and SN12C cells with phosphorothioate antisense p21 oligodeoxynucleotide markedly attenuated p21 and sensitized cells to the apoptosis induced by doxorubicin and cisplatin, such that an order of magnitude less of doxorubicin or cisplatin could be used in the presence of antisense to achieve equivalent or greater cell death. In addition, the mechanism of ACHN cell death associated with p21 attenuation involved decreases in the levels of anti-apoptotic proteins as well as an increase in the active form of the pro-apoptotic protein p53.ConclusionsSince phosphorothioate antisense oligodeoxynucleotides accumulate to a higher degree in the kidney and liver than in any other organ, our findings suggest a reevaluation of conventional chemotherapy in kidney cancer in association with antisense p21 oligodeoxynucleotide.