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Abstract：
Lung cancer is the leading cause of cancer mortality. Despite therapeutic advances in recent years, new treatment strategies are needed to improve outcomes of lung cancer patients. Mutant p53 is prevalent in lung cancers and drives several hallmarks of cancer through a gain-of-function oncogenic program, and often predicts a poorer prognosis. The oncogenicity of mutant p53 is related to its stability and accumulation in cells by evading degradation by the proteasome. Therefore, destabilization of mutant p53 has been sought as a therapeutic strategy, but so far without clinical success. In this study, we report that proteasome inhibition results in degradation of mutant p53 in non-small cell lung cancer (NSCLC) cell lines bearing the R273H mutant protein and show evidence that this was mediated by hsp70. NSCLC cell lines with the mutant R273H allele demonstrated increased susceptibility and apoptosis to proteasome inhibitors. These data suggest that proteasome inhibitors could have therapeutic implications in some subsets of TP53 mutated NSCLC.
摘要：
肺癌是癌症死亡的主要原因。尽管近年来的治疗进展，我们需要新的治疗策略来改善肺癌患者的预后.突变型p53在肺癌中普遍存在，并通过功能获得致癌程序驱动癌症的几个标志，并经常预测预后较差。突变型p53的致癌性与其通过逃避蛋白酶体降解而在细胞中的稳定性和积累有关。因此,已寻求突变p53的去稳定作为一种治疗策略，但到目前为止还没有临床成功。在这项研究中,我们报道,蛋白酶体抑制导致携带R273H突变蛋白的非小细胞肺癌(NSCLC)细胞系中突变p53的降解,并证明这是由hsp70介导的.具有突变R273H等位基因的NSCLC细胞系表现出对蛋白酶体抑制剂的敏感性和凋亡增加。这些数据表明蛋白酶体抑制剂可能在TP53突变的NSCLC的一些亚群中具有治疗意义。
