Wang Y, Blandino G, Oren M, Givol D
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Oncogene. 1998 Oct 15;17(15):1923-30. doi: 10.1038/sj.onc.1202113.
The p53-null human lung cancer cell line H1299 was used in order to generate clones with ecdysone-inducible p53 as well as ecdysone-inducible p21waf1. Induced expression of p53 resulted in irreversible cell growth arrest with characteristics of replicative senescence, suggesting that p53 can prevent immortalization by activating a senescence program. The effect of induced p53 and p21waf1 expression on the cytotoxic action of the anti-cancer drugs etoposide and cisplatin was also analysed. Whereas p21waf1 overexpression conferred increased resistance to killing by either drug, p53 overexpression enhanced the cytotoxic effect of cisplatin but protected against etoposide cytotoxicity. These results imply that the impact of p53 on susceptibility to chemotherapy may depend greatly on the particular drug and type of DNA damage. Moreover, these data demonstrate the importance of using isogenic cell lines to address this issue.
为了产生具有蜕皮激素诱导型p53以及蜕皮激素诱导型p21waf1的克隆，使用了p53基因缺失的人肺癌细胞系H1299。p53的诱导表达导致具有复制性衰老特征的不可逆细胞生长停滞，这表明p53可以通过激活衰老程序来防止细胞永生化。还分析了诱导型p53和p21waf1表达对抗癌药物依托泊苷和顺铂细胞毒性作用的影响。虽然p21waf1的过表达使细胞对这两种药物的杀伤具有更高的抗性，但p53的过表达增强了顺铂的细胞毒性作用，但对依托泊苷的细胞毒性具有保护作用。这些结果表明，p53对化疗敏感性的影响可能在很大程度上取决于特定的药物和DNA损伤类型。此外，这些数据证明了使用同基因细胞系来解决这个问题的重要性。
