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首页> 外文期刊>Scientific reports. >JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy
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JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy

机译:JNK通过诱导生存自噬使p53缺失和突变的p53表达结肠癌细胞具有5-氟尿嘧啶抗性

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摘要

Deficiency or mutation in the p53 tumor suppressor gene commonly occurs in human cancer and can contribute to disease progression and chemotherapy resistance. Currently, although the pro-survival or pro-death effect of autophagy remains a controversial issue, increasing data seem to support the idea that autophagy facilitates cancer cell resistance to chemotherapy treatment. Here we report that 5-FU treatment causes aberrant autophagosome accumulation in HCT116 p53?/? and HT-29 cancer cells. Specific inhibition of autophagy by 3-MA, CQ or small interfering RNA treatment targeting Atg5 or Beclin 1 can potentiate the re-sensitization of these resistant cancer cells to 5-FU. In further analysis, we show that JNK activation and phosphorylation of Bcl-2 are key determinants in 5-FU-induced autophagy. Inhibition of JNK by the compound SP600125 or JNK siRNA suppressed autophagy and phosphorylation of c-Jun and Bcl-2 but increased 5-FU-induced apoptosis in both HCT116 p53?/? and HT29 cells. Taken together, our results suggest that JNK activation confers 5-FU resistance in HCT116 p53?/? and HT29 cells by promoting autophagy as a pro-survival effect, likely via inducing Bcl-2 phosphorylation. These results provide a promising strategy to improve the efficacy of 5-FU-based chemotherapy for colorectal cancer patients harboring a p53 gene mutation.
机译:p53肿瘤抑制基因的缺乏或突变通常发生在人类癌症中,并可导致疾病进展和化疗耐药性。当前,尽管自噬的促生存或促死亡作用仍然是一个有争议的问题,但是越来越多的数据似乎支持自噬促进癌细胞对化学疗法治疗的抵抗力的观点。在这里我们报道5-FU治疗会导致HCT116 p53 ?/?和HT-29癌细胞中异常的自噬体积累。 3-MA,CQ或靶向Atg5或Beclin 1的小分子干扰RNA处理对自噬的特异性抑制作用可增强这些耐药癌细胞对5-FU的重新敏感性。在进一步的分析中,我们表明JNK激活和Bcl-2的磷酸化是5-FU诱导的自噬的关键决定因素。化合物SP600125或JNK siRNA抑制JNK抑制了c-Jun和Bcl-2的自噬和磷酸化,但增加了5-FU诱导的HCT116 p53 ?/?和HT29细胞的凋亡。两者合计,我们的结果表明JNK激活可能通过诱导自噬作为促生存作用,从而可能通过诱导Bcl-2磷酸化而赋予HCT116 p53 ?/?和HT29细胞5-FU耐药性。这些结果提供了一种有前途的策略,以提高基于5-FU的化疗对具有p53基因突变的结直肠癌患者的疗效。

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