Reactive Oxygen Species and Mitochondrial Sensitivity to Oxidative Stress Determine Induction of Cancer Cell Death by p21

Reactive Oxygen Species and Mitochondrial Sensitivity to Oxidative Stress Determine Induction of Cancer Cell Death by p21*

1. Ionica Masgras^‡,
2. Samantha Carrera^‡,
3. Petra J. de Verdier^§,
4. Paul Brennan^¶,
5. Aneela Majid^‖,
6. Wan Makhtar**,
7. Eugene Tulchinsky**,
8. George D. D. Jones**,
9. Igor B. Roninson^‡‡ and
10. Salvador Macip^‡,¹

+ Author Affiliations

1. From the ^‡Department of Biochemistry,
2. ^‖Medical Research Council (MRC) Toxicology Unit, and
3. ^**Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 9HN, United Kingdom,
4. the ^§Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institutet, 171 76 Stockholm, Sweden,
5. the ^¶Department of Infection, Immunity, and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom, and
6. the ^‡‡Translational Cancer Therapeutics Program Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208

1. ↵1 To whom correspondence should be addressed. Tel.: 44-0-116-228-7098; Fax: 44-0-116-229-7098; E-mail: sm460@le.ac.uk.

Capsule

Background: For unknown reasons, p21 expression induces different effects in cells, including arrest, death, and growth/prosurvival signals.

Results: Cancer cell lines respond with arrest or apoptosis to p21 expression depending on mitochondria sensitivity to oxidants.

Conclusion: Cell-specific sensitivity to oxidative stress determines p21-induced cell death.

Significance: This provides a rationale to find therapies that up-regulate p21 in cells that are more sensitive to oxidants to favor a death response.

Abstract

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.

• Apoptosis
• Cancer Therapy
• Oxidative Stress
• p53
• Reactive Oxygen Species (ROS)
• Senescence
• p21

Footnotes

• ↵* This work was supported, in whole or in part, by National Institutes of Health Grant R01 AG028687 (to I. B. R.). This work was also supported by New Blood Lectureship Research Support funding from the Medical Research Council (to S. M.), Consejo Nacional de Ciencia y Tecnologia (to S. C.), and the Swedish Cancer Society Grant Cancerfonden 2007/649 (to P. J. d. V.).
• ↵ This article contains supplemental Figs. 1–6.

• Received April 13, 2011.
• Revision received January 11, 2012.

• © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.