Cell cycle arrest of p53 can be used to convert p53 from killer to protector

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Nongenotoxic p53 Activation Protects Cells against S-Phase–Specific

Chemotherapy

Dominique Kranz1 and Matthias Dobbelstein1,2

1 Medical Biotechnology Center, Institute for Medical Biology,

University of Southern Denmark, Odense, Denmark and 2 Department of

Molecular Oncology, Göttingen Center of Molecular Biosciences,

University of Göttingen, Göttingen, Germany

Requests for reprints: Matthias Dobbelstein, Department of Molecular

Oncology, Göttingen Center of Molecular Biosciences, University of

Göttingen, Justus von Liebig Weg 11, D-37077 Göttingen, Germany.

Phone: 49-551-39-13840; Fax: 49-551-39-13713; E-mail: mdobbel@uni-

goettingen.de.

Mutations in the tumor suppressor gene TP53 represent the most

frequent genetic difference between tumor cells and normal cells.

Here, we have attempted to turn this difference into an advantage for

normal cells during therapy. Using the Mdm2 antagonist nutlin-3, we

first activated p53 in U2OS and HCT116 cells to induce cell cycle

arrest. These arrested cells were found to be resistant to subsequent

transient treatment with the nucleoside analogue gemcitabine, as

revealed by clonogenic assays following drug removal. In contrast,

isogenic cells lacking functional p53 continued to enter S phase

regardless of nutlin-3 pretreatment and remained highly susceptible

to gemcitabine-mediated cytotoxicity. The sequential treatment with

nutlin-3 alone, followed by transient exposure to nutlin-3 plus

gemcitabine, efficiently compromised the clonogenicity of tumor cells

with deletions or mutations of p53 but largely spared the

proliferation of nontransformed human keratinocytes. Nutlin-3

pretreatment also conferred protection of p53-proficient cells

against cytosine arabinoside but not against doxorubicin or

cisplatin. We propose that the cell cycle arrest function of p53 can

be used to convert p53 from a killer to a protector of cells, with

the potential to reduce unwanted side effects of chemotherapy.

(Cancer Res 2006; 66(21): 10274-80)