Cell Cycle Checkpoints (genetics); Cell Death (genetics); Cell Line, Tumor; Cellular Senescence (genetics); Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis, genetics); Gene Expression Regulation, Neoplastic; Humans; Mitochondria (genetics, metabolism, pathology); Oxidative Stress; Reactive Oxygen Species (metabolism); Sarcoma (genetics, metabolism, pathology); Tumor Suppressor Protein p53 (genetics, metabolism); Up-Regulation (genetics)
p21(Waf1/Cip1/Sdi1) is a cyclin-dependent kinase inhibitor that mediates cell cycle arrest. Prolonged p21 up-regulation induces a senescent phenotype in normal and cancer cells, accompanied by an increase in intracellular reactive oxygen species (ROS). However, it has been shown recently that p21 expression can also lead to cell death in certain models. The mechanisms involved in this process are not fully understood. Here, we describe an induction of apoptosis by p21 in sarcoma cell lines that is p53-independent and can be ameliorated with antioxidants. Similar levels of p21 and ROS caused senescence in the absence of significant death in other cancer cell lines, suggesting a cell-specific response. We also found that cells undergoing p21-dependent cell death had higher sensitivity to oxidants and a specific pattern of mitochondrial polarization changes. Consistent with this, apoptosis could be blocked with targeted expression of catalase in the mitochondria of these cells. We propose that the balance between cancer cell death and arrest after p21 up-regulation depends on the specific effects of p21-induced ROS on the mitochondria. This suggests that selective up-regulation of p21 in cancer cells could be a successful therapeutic intervention for sarcomas and tumors with lower resistance to mitochondrial oxidative damage, regardless of p53 status.
Digital Object Identifier (DOI)
Published in The Journal of Biological Chemistry, Volume 287, Issue 13, 2012, pages 9845-9854.
© 2012 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license.
Masgras, I., Carrera, S., de Verdier, P., Brennan, P., Majid, A., & Makhtar, W. et al. (2012). Reactive Oxygen Species and Mitochondrial Sensitivity to Oxidative Stress Determine Induction of Cancer Cell Death by p21. Journal Of Biological Chemistry, 287(13), 9845-9854. https://doi.org/10.1074/jbc.m111.250357