title: JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy.
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.
authors.affiliation: 1] Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China [2] Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China 310016 [3].
authors.forename: Xinbing
authors.initials: X
authors.lastname: Sui
authors.affiliation: 1] Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China [2] Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China 310016 [3].
authors.forename: Na
authors.initials: N
authors.lastname: Kong
authors.affiliation: 1] Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China [2] Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China 310016.
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China 310016.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Da
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Lou
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Gong
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 1] Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China [2] Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China 310016.
authors.forename: Hongming
authors.initials: H
authors.lastname: Pan
authors.affiliation: 1] Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China [2] Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China 310016.
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005472:Fluorouracil / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
chemical_list: C502778:ATG5 protein, human; D000873:Anthracenes; D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D005472:Fluorouracil
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