Inhibition of p53 increases chemosensitivity to 5-FU in nutrient-deprived hepatocarcinoma cells by suppressing autophagy.
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 pifithrin-α 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.
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China; Hang Zhou Sanitarium of Navy, Zhejiang, PR China.
Xian-ling
XL
Guo
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China; Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, PR China.
Fei
F
Hu
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
Shan-shan
SS
Zhang
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
Qiu-dong
QD
Zhao
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
Chen
C
Zong
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
Fei
F
Ye
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
Shi-wei
SW
Guo
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
Jian-wei
JW
Zhang
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
Rong
R
Li
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
Meng-chao
MC
Wu
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China. Electronic address: weilixin_smmu@163.com.
Li-xin
LX
Wei
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008930:Mitochondria, Liver / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D000964:Antimetabolites, Antineoplastic; D052160:Benzothiazoles; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; D005472:Fluorouracil
5FU; Autophagy; Hepatocarcinoma; Nutrient deprivation; p53