Reactive oxygen species and mitochondrial sensitivity to oxidative stress determine induction of cancer cell death by p21.
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.
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
Ionica
I
Masgras
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
Samantha
S
Carrera
Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institutet, 171 76 Stockholm, Sweden.
Petra J
PJ
de Verdier
Department of Infection, Immunity, and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom, and.
Paul
P
Brennan
Medical Research Council (MRC) Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom.
Aneela
A
Majid
Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 9HN, United Kingdom.
Wan
W
Makhtar
Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 9HN, United Kingdom.
Eugene
E
Tulchinsky
Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 9HN, United Kingdom.
George D D
GDD
Jones
Translational Cancer Therapeutics Program Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208.
Igor B
IB
Roninson
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom. Electronic address: sm460@le.ac.uk.
Salvador
S
Macip
D059447:Cell Cycle Checkpoints / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53