Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism

Jie Huang; Jianqi Yang; Biswanath Maity; Daisuke Mayuzumi; Rory A Fisher

doi:10.1158/0008-5472.CAN-10-3397

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Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism

Journal article

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Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism

Jie Huang, Jianqi Yang, Biswanath Maity, Daisuke Mayuzumi and Rory A Fisher

Cancer research (Chicago, Ill.), Vol.71(20), pp.6310-6319

10/15/2011

DOI: 10.1158/0008-5472.CAN-10-3397

PMCID: PMC3196377

PMID: 21859827

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Abstract

Doxorubicin (DXR), among the most widely used cancer chemotherapy agents, promotes cancer cell death via activation of ataxia telangiectasia mutated (ATM) and the resultant upregulation of tumor suppressor p53. The exact mechanism by which DXR activates ATM is not fully understood. Here, we discovered a novel role for regulator of G protein signaling 6 (RGS6) in mediating activation of ATM and p53 by DXR. RGS6 was robustly induced by DXR, and genetic loss of RGS6 dramatically impaired DXR-induced activation of ATM and p53, as well as its in vivo apoptotic actions in heart. The ability of RGS6 to promote p53 activation in response to DXR was independent of RGS6 interaction with G proteins but required ATM. RGS6 mediated activation of ATM and p53 by DXR via a reactive oxygen species (ROS)-dependent and DNA damage-independent mechanism. This mechanism represents the primary means by which DXR promotes activation of the ATM-p53 apoptosis pathway that underlies its cytotoxic activity. Our findings contradict the canonical theories that DXR activates ATM primarily by promoting DNA damage either directly or indirectly (via ROS) and that RGS6 function is mediated by its interactions with G proteins. These findings reveal a new mechanism for the chemotherapeutic actions of DXR and identify RGS6 as a novel target for cancer chemotherapy.

Tumor Suppressor Proteins - metabolism

Reactive Oxygen Species - metabolism

Apoptosis - drug effects

Cell Cycle Proteins - metabolism

Tumor Suppressor Protein p53 - metabolism

Ataxia Telangiectasia Mutated Proteins

DNA-Binding Proteins - metabolism

Animals

RGS Proteins - metabolism

Antineoplastic Agents - pharmacology

Mice

Tumor Cells, Cultured

Doxorubicin - pharmacology

Protein-Serine-Threonine Kinases - metabolism

Fibroblasts - metabolism

Details

Title: Subtitle: Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism
Creators: Jie Huang - Department of Pharmacology, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
Jianqi Yang
Biswanath Maity
Daisuke Mayuzumi
Rory A Fisher
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.71(20), pp.6310-6319
DOI: 10.1158/0008-5472.CAN-10-3397
PMID: 21859827
PMCID: PMC3196377
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: R01 GM075033-03 / NIGMS NIH HHS GM075033 / NIGMS NIH HHS R01 GM075033 / NIGMS NIH HHS GM075033-03S1 / NIGMS NIH HHS R01 GM075033-03S1 / NIGMS NIH HHS
Language: English
Date published: 10/15/2011
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040315102771

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