Induction of cell cycle arrest by GL331 via triggering an ATM-dependent DNA damage response in HepG2 cells

Abstract

GL331, a topoisomerase II inhibitor, has been found to trigger DNA damage response (DDR) to induce cell cycle arrest. However, the underlying mechanism has not yet been fully understood. This study investigated the molecular mechanism involved in the GL331-induced cell cycle arrest via DDR in human hepatocellular carcinoma HepG2 cells. As a result, GL331 could induce S arrest and up-regulate the phosphorylation of the histone H2AX variant (γ-H2AX). Ataxia telangiectasia mutated protein kinase (ATM) was activated by GL331 through its autophosphorylation at Ser1981, which led to the activation of DNA damage signaling pathways including p53/p21 and Chk2/Cdc25A cascades. The DNA damage cascades triggered by GL331 finally induced the inactivation of cyclin A/Cdk2 complexes to some extent. These phenomena could be reversed by ATM siRNA, followed by a partial disruption of S arrest. The present results suggested that the S arrest induced by GL331 via DDR was in an ATM-dependent manner to some degree.

Keywords:

• GL331
• cell cycle
• ATM
• p53
• Chk2

Acknowledgments

This study was financially supported by Important National Science & Technology Specific Projects (2009ZX09301-003-9-1) grant from the Ministry of Science and Technique of China. We would like to dedicate this manuscript to the memory of Academician Geng-Tao Liu, who unfortunately passed away during the preparation of this manuscript.