Inhibition of p53 increases chemosensitivity to 5-FU in nutrient-deprived hepatocarcinoma cells by suppressing autophagy

被引:35
作者
Guo, Xian-ling [1 ,2 ]
Hu, Fei [1 ,3 ]
Zhang, Shan-shan [1 ]
Zhao, Qiu-dong [1 ]
Zong, Chen [1 ]
Ye, Fei [1 ]
Guo, Shi-wei [1 ]
Zhang, Jian-wei [1 ]
Li, Rong [1 ]
Wu, Meng-chao [1 ]
Wei, Li-xin [1 ]
机构
[1] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Tumor Immunol & Gene Therapy Ctr, Shanghai 200438, Peoples R China
[2] Hang Zhou Sanitarium Navy, Hangzhou, Zhejiang, Peoples R China
[3] Tongji Univ, Sch Med, Dept Med Oncol, Shanghai Peoples Hosp 10, Shanghai 200092, Peoples R China
基金
中国国家自然科学基金;
关键词
Autophagy; p53; Hepatocarcinoma; 5FU; Nutrient deprivation; PROTEIN; DISEASE; ACTIVATION; MECHANISMS; THERAPY; HEALTH;
D O I
10.1016/j.canlet.2014.01.011
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:278 / 284
页数:7
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