title: Activation of anaphase-promoting complex by p53 induces a state of dormancy in cancer cells against chemotherapeutic stress.
abstract: Cancer dormancy is a stage in tumor progression in which residual disease remains occult and asymptomatic for a prolonged period. Cancer cell dormancy is the main cause of cancer recurrence and failure of therapy. However, cancer dormancy is poorly characterized and the mechanisms of how cancer cells develop dormancy and relapse remain elusive. In this study, 5- fluorouracil (5-FU) was used to induce cancer cell dormancy. We found that cancer cells escape the cytotoxicity of 5-FU by becoming "dormant". After exposure to 5-FU, residual non-small cell lung cancer (NSCLC) cells underwent epithelial-mesenchymal transition (EMT), followed by mesenchymal-epithelial transition (MET). These EMT-transformed NSCLC cells were in the state of cell quiescence where cells were not dividing and were arrested in the cell cycle in G0-G1. The dormant cells underwent an EMT showed characteristics of cancer stem cells. P53 is strongly accumulated in response to 5-FU-induced dormant cells through the activation of ubiquitin ligase anaphase-promoting complex (APC/C) and TGF-β/Smad signaling. In contrast to the EMT-transformed cells, MET-transformed cells showed an increased ability to proliferate, suggesting that dormant EMT cells were reactivated in the MET process. During the EMT-MET process, DNA repair including nonhomologous end joining (NHEJ) and homologous recombination (HR) is critical to dormant cell reactivation. Our findings provide a mechanism to unravel cancer cell dormancy and reactivation of the cancer cell population.
authors.affiliation: Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China.|Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.
authors.forename: Lujuan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Jingqun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Cao
authors.affiliation: Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.|Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.affiliation: Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.
authors.forename: Abraha
authors.initials: A
authors.lastname: Kiflu
authors.affiliation: Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.
authors.forename: Buqing
authors.initials: B
authors.lastname: Sai
authors.affiliation: Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.
authors.forename: Meili
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China.|Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, PR China.
authors.forename: Guiyuan
authors.initials: G
authors.lastname: Li
authors.affiliation: Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China.|Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, Changsha, Hunan, PR China.|Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, PR China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Xiang
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D018365:Neoplasm, Residual; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D064173:Anaphase-Promoting Complex-Cyclosome; D005472:Fluorouracil
keywords: DNA repair; Smad2; cancer dormancy; drug resistance; p53