title: Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism.
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.
authors.affiliation: Department of Pharmacology, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Jianqi
authors.initials: J
authors.lastname: Yang
authors.forename: Biswanath
authors.initials: B
authors.lastname: Maity
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mayuzumi
authors.forename: Rory A
authors.initials: RA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D020710:RGS Proteins; D017382:Reactive Oxygen Species; C485692:Rgs6 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases