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

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

doi:10.18632/oncotarget.8172

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.

Highlights

Patients with cancer can develop local or disseminated recurrence after therapy and long periods of latency, which is a major obstacle preventing cure and long-term survival in patients [1]
We found that cancer cells that escape cytotoxicity of 5- fluorouracil (5-FU) by becoming “dormant” displayed epithelial-mesenchymal transition (EMT) followed by mesenchymalepithelial transition (MET)
Cancer cells escaping cytotoxicity of 5-FU undergo EMT followed by MET

Summary

Introduction

Patients with cancer can develop local or disseminated recurrence after therapy and long periods of latency, which is a major obstacle preventing cure and long-term survival in patients [1]. This latency can be explained by cancer dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic [1]. Cancer cell dormancy is the main cause of cancer recurrence and failure of therapy [2,3]. Cancer dormancy is characteristic of cell quiescence where cells are not dividing but at arrest in the cell cycle in G0-G1. Oncogenic signaling might not always be dominant and stem cell quiescence and stress signaling could overcome oncogenic signals, allowing tumor cell survival in a dormant state [1]

Methods

Results

Conclusion