Regulator of G protein Signaling 6 (RGS6) is Upregulated in Cancer cells by Doxorubicin and Modulates Doxorubicin‐induced DNA damage signaling

Abstract

RGS proteins were discovered as negative regulators of heterotrimeric G protein signaling. The precise biological role of all but a few RGS proteins is unknown, as is the need for such a large structurally diverse protein family if RGS proteins function only as G protein GAPs. Here, we provide new evidence suggesting a role of RGS6 in regulating DNA damage responses in cancer cells. Doxorubicin (Dox) treatment of cancer cell lines led to dramatic increases in RGS6 protein levels, which were undetectable in unstimulated cells. Dox induction of RGS6 protein was accompanied by significant increase in RGS6 gene transcription as assessed using an RGS6 gene promoter reporter. Further, expression of RGS6 in MCF7 cells promoted phosphorylation of p53 in response to a low dose of Dox, which alone had no effects. This activity of RGS6 requires its DEP domain but is independent of its interaction with G proteins. RGS6 expression in several cancer cell lines promoted cell cycle arrest and growth suppression. ATM, an upstream activator of p53, may be involved in RGS6‐induced p53 phosphorylation, as expression of RGS6 promotes ATM activation in response to a submaximal dose of Dox. Our data identify RGS6 as a target of Dox and suggest that RGS6 may play a novel role as a modulator of chemosensitivity in cancer cells. Importantly, these actions of RGS6 are independent of its interaction with G proteins.NIH (GM075033) and AHA (0750057Z).