Research Papers:

Activation of anaphase-promoting complex by p53 induces a state of dormancy in cancer cells against chemotherapeutic stress

Yafei Dai, Lujuan Wang, Jingqun Tang, Pengfei Cao, Zhaohui Luo, Jun Sun, Abraha Kiflu, Buqing Sai, Meili Zhang, Fan Wang, Guiyuan Li and Juanjuan Xiang _

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Oncotarget. 2016; 7:25478-25492. https://doi.org/10.18632/oncotarget.8172

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Yafei Dai1,2, Lujuan Wang2, Jingqun Tang3, Pengfei Cao2, Zhaohui Luo2,5, Jun Sun2, Abraha Kiflu2, Buqing Sai2, Meili Zhang2, Fan Wang2, Guiyuan Li1,2,4, Juanjuan Xiang1,2,4

1Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China

2Cancer 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

3Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China

4Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, PR China

5Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China

Correspondence to:

Juanjuan Xiang, e-mail: [email protected]

Guiyuan Li, e-mail: [email protected]

Keywords: cancer dormancy, drug resistance, p53, Smad2, DNA repair

Received: November 16, 2015    Accepted: March 02, 2016    Published: March 18, 2016


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.

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