Many chemotherapeutic drugs kill only a fraction of cancer cells, limiting their efficacy. We used live-cell imaging to investigate the role of p53 dynamics in fractional killing of colon cancer cells in response to chemotherapy. We found that both surviving and dying cells reach similar levels of p53, indicating that cell death is not determined by a fixed p53 threshold. Instead, a cell's probability of death depends on the time and levels of p53. Cells must reach a threshold level of p53 to execute apoptosis, and this threshold increases with time. The increase in p53 apoptotic threshold is due to drug-dependent induction of anti-apoptotic genes, predominantly in the inhibitors of apoptosis (IAP) family. Our study underlines the importance of measuring the dynamics of key players in response to chemotherapy to determine mechanisms of resistance and optimize the timing of combination therapy.
Bibliographical noteFunding Information:
We thank T. Weinert, U. Alon, and S. Gaudet for comments and discussions; G. Gaglia for the p21 promoter construct, S. Chen, J. Stewart-Ornstein, A. Iagovitina, and J. Reyes for advice on figures; J. Porter for support and encouragement; A. Kedves for help with initial cisplatin studies; the Nikon Imaging Center at Harvard Medical School for help with microscopy; and members of the Lahav lab for comments and discussion. This research was supported by Novartis Institutes for Biomedical Research and NIH grant GM083303 . A.L.P. was supported by an American Cancer Society New England Division-Ellison Foundation Postdoctoral Fellowship . J.C.L. was supported by the Molecular Biophysics Training Grant ( NIH/NIGMS T32008313 ) and the National Science Foundation Graduate Research Fellowship .