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

被引：18

作者：

Mohanty, S. ^{[1
]}

Saha, S. ^{[1
]}

Hossain, D. Md S. ^{[1
]}

Adhikary, A. ^{[1
]}

Mukherjee, S. ^{[1
]}

Manna, A. ^{[1
]}

Chakraborty, S. ^{[1
]}

Mazumdar, M. ^{[1
]}

Ray, P. ^{[1
]}

Das, K. ^{[1
]}

Chakraborty, J. ^{[1
]}

Sa, G. ^{[1
]}

Das, T. ^{[1
]}

机构：

[1] Bose Inst, Div Mol Med, Kolkata 700054, India

来源：

CELL DEATH & DISEASE | 2014年 / 5卷

关键词：

apoptosis; drug resistance; ROS; NF kappa B; IKK gamma; PIAS gamma; NF-KAPPA-B; CHRONIC LYMPHOCYTIC-LEUKEMIA; NECROSIS-FACTOR-ALPHA; T-CELL APOPTOSIS; DNA-DAMAGE; OXIDATIVE STRESS; ATAXIA-TELANGIECTASIA; GLIOBLASTOMA CELLS; GENE-EXPRESSION; CANCER;

D O I：

10.1038/cddis.2013.534

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 gamma interaction induced NF kappa 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 PIASc, thereby disrupting PIAS gamma-IKK gamma cross talk, a pre-requisite for IKK gamma sumoylation and subsequent NF kappa B activation. Interruption in the PIAS gamma-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 gamma 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 gamma in regulating ATM-mediated chemosensitization of resistant tumors. Thus, therapeutic strategies employing ROS upregulation to inhibit PIASc during genotoxic therapy may, in future, help to eliminate the problems of NFjB-mediated tumor drug resistance.

引用

页码：e1021 / e1021

页数：12

共 53 条

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