Drug-induced apoptosis occurs after cells reach a p53 threshold level, which increases over time.
Major finding: Drug-induced apoptosis occurs after cells reach a p53 threshold level, which increases over time.
Mechanism: A slow rate of p53 induction upregulates IAP proteins and increases the p53 apoptotic threshold.
Impact: Hastening p53 induction or reducing the p53 apoptotic threshold may enhance chemotherapy potency.
One of the primary barriers to efficacious cancer therapy is chemotherapy resistance of a subset of tumor cells that can be driven by both genetic and nongenetic mechanisms. Two of the nongenetic mechanisms of resistance are linked to cell-cycle effects or the temporal dynamics of critical factors in response to drug treatment. This resistance results in the phenomenon known as fractional killing, in which a constant fraction of tumor cells, regardless of tumor size, survives after one round of chemotherapy. The tumor suppressor p53 is a critical factor in the cellular response to chemotherapy-induced DNA damage, and can drive either DNA repair or apoptosis depending upon the pattern of temporal changes in p53 levels. To elucidate the role of p53 dynamics in chemotherapy-mediated fractional killing, Paek and colleagues performed live-cell tracking of p53 in isogenic colon cancer cell lines treated with cisplatin. Rapid p53 accumulation was associated with apoptotic cell death once a cell reached a p53 threshold level, which increased with time after cisplatin treatment. Consistent with these findings, treatment with nutlin3, which stabilizes p53, accelerated p53 accumulation after cisplatin treatment and resulted in increased apoptotic cell death, compared to treatment with cisplatin alone. The increase in the p53 apoptotic threshold level over time was not due to p53 induction of apoptotic and cell-cycle genes, but due to cisplatin-mediated upregulation of inhibitors of apoptosis (IAP) proteins. Combined treatment of colon cancer cells with cisplatin and an IAP inhibitor both lowered and flattened the p53 apoptotic threshold. Taken together, these results show that fractional cell killing is due to cell-to-cell variability in p53 dynamics and suggests that profiling single cell–specific p53 dynamics in a tumor may inform the optimization of drug dosing schedules and improve chemotherapy efficacy.