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Reactive oxygen species and mitochondrial sensitivity to oxidative stress determine induction of cancer cell death by p21.

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journal contribution
posted on 24.10.2012, 08:55 by Ionica Masgras, Samantha Carrera, Petra J. de Verdier, Paul Brennan, Aneela Majid, Wan Makhtar, Eugene Tulchinsky, George D. D. Jones, Igor B. Roninson, Salvador Macip
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.

History

Citation

J BIOL CHEM, 2012, 287 (13), pp. 9845-9854

Published in

J BIOL CHEM

Publisher

American Society for Biochemistry and Molecular Biology

issn

0021-9258

eissn

1083-351X

Copyright date

2012

Available date

24/10/2012

Publisher version

http://www.jbc.org/content/287/13/9845

Notes

See also http://hdl.handle.net/2381/12655 metadata record

Language

eng