Mutant p53 exhibits trivial effects on mitochondrial functions which can be reactivated by ellipticine in lymphoma cells.
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.
Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, LA 71130, USA.
Fei
F
Wang
Jianfeng
J
Liu
Delira
D
Robbins
Kerri
K
Morris
Amos
A
Sit
Yong-Yu
YY
Liu
Yunfeng
Y
Zhao
D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D004611:Ellipticines / Q000494:pharmacology*; D006801:Humans; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D004611:Ellipticines; D050505:Mutant Proteins; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; C034192:ellipticine; D004317:Doxorubicin; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I