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- Title
JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy.
- Authors
Xinbing Sui; Na Kong; Xian Wang; Yong Fang; Xiaotong Hu; Yinghua Xu; Wei Chen; Kaifeng Wang; Da Li; Wei Jin; Fang Lou; Yu Zheng; Hong Hu; Liu Gong; Xiaoyun Zhou; Hongming Pan; Weidong Han
- Abstract
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.
- Subjects
FLUOROURACIL; ANTINEOPLASTIC agents; GENETIC mutation; GENE expression; AUTOPHAGY; CANCER chemotherapy
- Publication
Scientific Reports, 2014, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/srep04694