The contribution of p53 in the dynamics of cell cycle response to DNA damage interpreted by a mathematical model.
Despite numerous studies on the tumor suppressor p53, a complete picture of its role in cell arrest and killing in G(1), S and G(2)M phases after drug treatment is lacking. We tackled the analysis of the complexity of cell cycle effects combining the time-course measures with different techniques with the aid of a computer program simulating cell cycle progression. This mixed experimental-simulation approach enabled us to decode the dynamics of the cytostatic and cytotoxic responses to cisplatin and doxorubicin treatments in a p53--proficient colon carcinoma cell line (HCT-116) and in its p53-deficient counterpart. We achieved a separate evaluation of the activity of each cell cycle control and we connected these results with measures of p53 level in G(1), S and G(2)M. We confirmed the action of p53 in all cell cycle phases, but also the presence of strong p53-independent cytostatic and cytotoxic activities exerted by both drugs. In G(1) phase, p53 was responsible for a medium/long term block, distinct from the short-term block, which was p53-independent. The delay in traversing S phase was reduced by the presence of p53. In G(2)M phase, despite a strong p53-independent block, there was a weaker but more persistent p53-dependent block. At cytotoxic concentrations, p53-dependent and p53-independent cell death was observed. The former was poorly phase-specific, occurred earlier and exploited the apoptotic mechanism more than p53-independent death. Computer simulation produced a framework where previous partial and sometimes apparently contradictory observations of the p53-mediated effects could be reconciled and explained.
Lupi
Monica
M
Biophysics Unit, Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Matera
Giada
G
Natoli
Claudia
C
Colombo
Valentina
V
Ubezio
Paolo
P
D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D003198:Computer Simulation; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity; D045325:HCT116 Cells; D006801:Humans; D008962:Models, Theoretical; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002945:Cisplatin