ROS-PIAS? cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors.

ABSTRACT: With the existing knowledge of ATM's role in therapeutic resistance, the present study aimed at identifying the molecular mechanisms that influence ATM to oscillate between chemoresistance and chemosensitivity. We observed that the redox status of tumors functions as a major determinant of ATM-dependent 'resistance-to-apoptosis' molecular switch. At a low reactive oxygen species (ROS) condition during genotoxic insult, the ATM/sumoylated-IKK? interaction induced NF?B activation that resisted JNK-mediated apoptosis, whereas increasing cellular ROS restored ATM/JNK apoptotic signaling. A search for the upstream missing link revealed that high ROS induces oxidation and ubiquitin-mediated degradation of PIAS?, thereby disrupting PIAS?-IKK? cross talk, a pre-requisite for IKK? sumoylation and subsequent NF?B activation. Interruption in the PIAS?-mediated resistance pathway channels ATM signaling toward ATM/JNK pro-death circuitry. These in vitro results also translated to sensitive and resistant tumor allograft mouse models in which low ROS-induced resistance was over-ruled in PIAS? knockout tumors, while its overexpression inhibited high ROS-dependent apoptotic cues. Cumulatively, our findings identified an unappreciated yet critical combinatorial function of cellular ROS and PIAS? in regulating ATM-mediated chemosensitization of resistant tumors. Thus, therapeutic strategies employing ROS upregulation to inhibit PIAS? during genotoxic therapy may, in future, help to eliminate the problems of NF?B-mediated tumor drug resistance.

SUBMITTER: Mohanty S 

PROVIDER: S-EPMC4040699 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature