RT Journal Article
SR Electronic
T1 Variable sensitivity to DNA damaging chemotherapeutic modulated by cell type-dependent bimodal p53 dynamics
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 149013
DO 10.1101/149013
A1 Ruizhen Yang
A1 Bo Huang
A1 Yanting Zhu
A1 Yang Li
A1 Feng Liu
A1 Jue Shi
YR 2017
UL http://biorxiv.org/content/early/2017/06/12/149013.abstract
AB Mechanisms that determine drug sensitivity of distinct cancer types is poorly understood for most cytotoxic chemotherapy. In this study, we elucidated a new resistance mechanism to DNA damaging chemotherapeutic through modulation of p53 dynamics. While both sensitive and resistant cancer cell lines activated similar p53 oscillation followed by cell-cycle arrest in response to low dose of DNA damaging drug, they switched in a bimodal manner to monotonic or single pulse dynamics at high drug dose. Cell lines with monotonically increasing p53 underwent rapid and extensive drug-induced apoptosis, while those exhibiting a single p53 pulse mostly survived. By combining single cell imaging with computational modeling, we characterized a regulatory module involving ATM, p53, Mdm2 and Wip1, which generates bimodal p53 dynamics through coupled feed-forward and feedback, and we found that basal expression of ATM determined the differential modular output between drug sensitive and resistant lines. Moreover, we showed combinatorial inhibition of Mdm2 and Wip1 was an effective strategy to alter p53 dynamics in resistant cancer cells and sensitize their apoptotic response. Our results point to p53 pulsing as a potentially druggable mechanism that mediates resistance to cytotoxic chemotherapy.