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 ATM and the resultant up-regulation 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 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.

Emodin-Provoked Oxidative Stress Induces Apoptosis in Human Colon Cancer HCT116 Cells through a p53-Mitochondrial Apoptotic Pathway

“…It should be noted that ROS elicited by emodin may not upregualte p53 expression directly. In cancer cells excessive intercellular ROS often induces oxidative DNA damage, which activates ATM and subsequently promotes p53 expression (Guo et al, 2010;Huang et al, 2011).…”

Changing of RGS Transcripts Levels by Low-Dose-Rate Ionizing Radiation in Mouse Testis

“…Under cellular stress conditions, such as proteasome-mediated stress or mild heat stress, RGS6 is translocated into the nucleoli [24]. RGS6 also modulates doxorubicin-mediated ATM and p53 activation [25] and suppressed breast cancer initiation and progression [26]. Furthermore, the indirect interaction of RGS6 and DNA methyltransferase (Dnmt1), which is considered as a novel oncogene that suppresses the transcription of pro-apoptotic genes, have also been reported [27].…”

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

“…Interestingly, experiments conducted to test this hypothesis not only confirmed that RGS6 facilitates DDR but that RGS6 is absolutely required for Dox-mediated activation of the ataxia telangiectasia mutant (ATM)-p53-apoptotic cascade in both mouse embryonic fibroblasts (MEFs) and the MCF-7 breast cancer cell line (30). First, it was found that Dox administration led to an upregulation in RGS6, which was accompanied by both the phosphorylation and upregulation of p53.…”

“…In particular, RGS6−/− mice chronically exposed to alcohol lacked alcohol-induced cardiac hypertrophy and fibrosis, hepatic steatosis, and gastrointestinal barrier dysfunction and endotoxemia. This reduction in alcohol-induced peripheral tissue damage is believed to involve RGS6's direct or indirect regulation of reactive oxygen species (ROS) production and the apoptotic cascade (21) similar to its functions in cancer suppression (27)(28)(29)(30).…”

“…RGS6 specific modulation of Gα i/o protein activity has been implicated in the regulation of several disease states, particularly in the central nervous system (CNS), including the following: alcoholism (21), anxiety/depression (22), Parkinson's disease (23), and potentially Alzheimer's disease (24), schizophrenia (25), and vision (26). However, RGS6 is also unique in that it remains the only member of the R7 protein family that has been demonstrated to regulate G protein-independent pathways, as evidenced by its compelling pro-apoptotic and tumor suppressor actions in cancer (27)(28)(29)(30).…”