期刊
CANCER LETTERS
卷 346, 期 2, 页码 278-284出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2014.01.011
关键词
Autophagy; p53; Hepatocarcinoma; 5FU; Nutrient deprivation
类别
资金
- Key Basic Research Project of China [2012CBA01303, 2011CB966200, 2010CB945600, 2011CB965100]
- National Natural Science Foundation of China [81030041, 81000970, 31171321, 81101622]
- Special Funds for National key Sci-Tech Sepcial Project of China [2012ZX10002-016, 2012ZX10002011-011]
- Shanghai Science and Technology Committee [10ZR1439600, 11ZR1449500, 11nm0504700]
- Shanghai Municipal Health Bureau [XYQ2011044, 20114004]
- Science Fund for Creative Research Groups, NSFC, China [81221061]
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.
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