Inhibition of p53 increases chemosensitivity to 5-FU in nutrient-deprived hepatocarcinoma cells by suppressing autophagy
Inhibition of p53 increases chemosensitivity to 5-FU in nutrient-deprived hepatocarcinoma cells by suppressing autophagy
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抑制 p53 通过抑制自噬增加营养缺乏的肝癌细胞对 5-FU 的化学敏感性
DOI：
10.1016/j.canlet.2014.01.011
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发表时间：
2014-05-01
期刊：
影响因子：
9.7
通讯作者：
Wei, Li-xin
中科院分区：
文献类型：
--
作者：
Guo, Xian-ling;Hu, Fei;Wei, Li-xin
p53的激活可以诱导细胞凋亡、细胞周期停滞和细胞衰老，尽管一些证据表明p53可以促进细胞存活。然而，p53是否在化疗的癌细胞存活中起积极作用仍然未知。在这项研究中，我们发现，抑制p53增强细胞凋亡和5-氟尿嘧啶（5-FU）在营养缺乏的肝癌细胞（HCC）的化疗敏感性增加。同时，营养剥夺诱导的自噬被piflthrin-alpha或靶向p53的小干扰RNA抑制。p53的表达没有增加时，肝癌在营养缺乏的条件下孵育。这表明p53的基础水平对于营养缺乏的HCC细胞中的自噬激活是重要的。此外，结合p53抑制和营养剥夺或5-FU治疗导致活性氧产生和线粒体损伤显着增加。抗氧化剂减少营养剥夺或5-FU诱导的肝癌细胞死亡后，p53抑制。我们的研究结果表明，p53通过调节自噬激活，在营养缺乏的条件下，有助于肝癌细胞的存活和化疗耐药性。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Activation of p53 can induce apoptosis, cell cycle arrest, and cell senescence, although some evidence has suggested that p53 could promote cell survival. However, whether p53 plays a positive role in cancer cell survival to chemotherapy remains unknown. In this study, we show that inhibition of p53 enhanced apoptosis and increased chemosensitivity to 5-fluorouracil (5-FU) in nutrient-deprived hepatocarcinoma cells (HCC). Meanwhile, nutrient-deprivation-induced autophagy was inhibited by piflthrin-alpha or small interfering RNA targeting p53. The expression of p53 was not increased when HCC were incubated under nutrient-deprived conditions. This indicates that the basal level of p53 is important to autophagy activation in nutrient-deprived HCC cells. Furthermore, combining p53 inhibition and nutrient deprivation or 5-FU treatment resulted in a marked increase in reactive oxygen species generation and mitochondrial damage. Antioxidants reduced nutrient deprivation or 5-FU-induced cell death of HCC after p53 inhibition. Our results suggest that p53 contributes to cell survival and chemoresistance in HCC under nutrient-deprived conditions by modulating autophagy activation. (C) 2014 Elsevier Ireland Ltd. All rights reserved.