Abstract
Increasing evidence has shown that a fraction of the wild-type (wt) form of the tumor suppressor p53, can translocate to mitochondria due to genotoxic stress. The mitochondrial targets of wt p53 have also been studied. However, whether mutant p53, which exists in 50% of human cancers, translocates to mitochondria and affects mitochondrial functions is unclear. In this study, we used doxorubicin, a chemotherapeutic drug, to treat five human lymphoma cell lines with wt, mutant or deficient in p53, to induce p53 activation and mitochondrial translocation. Our results demonstrated that mutant p53, like wt p53, was induced upon doxorubicin treatment. Similarly, a fraction of mutant p53 also translocated to mitochondria. However, Complex I and II activities in the mitochondria were compromised only in wt p53-bearing cells after doxorubicin treatment, but not in mutant p53-bearing cells. Similarly, doxorubicin treatment caused greater cell death only in wt p53-bearing cells, but not in mutant p53-bearing cells. When p53 deficient Ramos cells were transfected with mutant p53 (249S), the cells showed resistance to doxorubicin-induced cell death and decreases in complex activities. To reactivate mutant p53 and reverse chemoresistance, ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) was used to treat mutant p53 cells. Ellipticine enhanced p53 mitochondrial translocation, decreased Complex I activity, and sensitized p53 mutant cells to doxorubicin-induced apoptosis. In summary, our studies suggest that mutations in p53 may not hinder p53’s mitochondrial translocation, but impair its effects on mitochondrial functions. Therefore, restoring mutant p53 by ellipticine may sensitize these cells to chemotherapy.
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Acknowledgment
The authors would like to thank Dr. Mitchell Smith at Fox Chase Cancer Center, Philadelphia, PA, for providing us with human lymphoma B-cell lines DoHH2; and Dr. Heinz Kohler at the University of Kentucky for providing Raji, DHL-4, Romas, and JOK-1 cells. We also would like to thank Rachael Walton (C.E. Byrd High School, Shreveport, LA) and Adrienne Parker (Wiley College, Marshall, TX) for their technical support. This work was supported by Grant Number R03CA128077 from the National Cancer Institute and Grant Number NSF(2010)-PFUND-199 from the Louisiana Board of Regents.
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Wang, F., Liu, J., Robbins, D. et al. Mutant p53 exhibits trivial effects on mitochondrial functions which can be reactivated by ellipticine in lymphoma cells. Apoptosis 16, 301–310 (2011). https://doi.org/10.1007/s10495-010-0559-8
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DOI: https://doi.org/10.1007/s10495-010-0559-8