Reactive oxygen species generation is essential for cisplatin-induced accelerated senescence in hepatocellular carcinoma

Abstract

Accelerated senescence is important because this process is involved in tumor suppression and has been induced by many chemotherapeutic agents. The platinum-based chemotherapeutic agent cisplatin displays a wide range of antitumor activities. However, the molecular mechanism of cisplatin-induced accelerated senescence in hepatocellular carcinoma (HCC) remains unclear. In the present study, the growth inhibitory effect of cisplatin on HepG2 and SMMC-7721 cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cellular senescence was then assessed by β-galactosidase assay. Senescence-related factors, including p53, p21, and p16, were evaluated by quantitative reverse transcription-polymerase chain reaction. Reactive oxygen species (ROS) was analyzed by flow cytometry. Our results revealed that cisplatin reduced the proliferation of HepG2 and SMMC-7721 cells in a dose- and time-dependent manner. Senescent phenotype observed in cisplatin-treated hepatoma cells was dependent on p53 and p21 activation but not on p16 activation. Furthermore, cisplatin-induced accelerated senescence depended on intracellular ROS generation. The ROS scavenger N-acetyl-L-cysteine also significantly suppressed the cisplatin-induced senescence of HepG2 and SMMC-7721 cells. In conclusion, our results revealed a functional link between intracellular ROS generation and cisplatin-induced accelerated senescence, and this link may be used as a potential target of HCC.

Keywords

reactive oxygen species / senescence / cisplatin / hepatocellular carcinoma

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81201549 and 81272644).

Compliance with ethics guidelines

Kai Qu, Ting Lin, Zhixin Wang, Sinan Liu, Hulin Chang, Xinsen Xu, Fandi Meng, Lei Zhou, Jichao Wei, Minghui Tai, Yafeng Dong, and Chang liu declare that they have no conflict of interest. This manuscript does not involve a research protocol requiring approval from relevant institutional review board or ethics committee.

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2014 Higher Education Press and Springer-Verlag Berlin Heidelberg