title: Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells.
abstract: The regulator of G protein signaling 10 (RGS10) protein is a GTPase activating protein that accelerates the hydrolysis of GTP and therefore canonically inactivates G proteins, ultimately terminating signaling. Rheb is a small GTPase protein that shuttles between its GDP- and GTP-bound forms to activate mTOR. Since RGS10 suppression augments ovarian cancer cell viability, we sought to elucidate the molecular mechanism. Following RGS10 suppression in serum-free conditions, phosphorylation of mTOR, the eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), p70S6K and S6 Ribosomal Protein appear. Furthermore, suppressing RGS10 increases activated Rheb, suggesting RGS10 antagonizes mTOR signaling via the small G-protein. The effects of RGS10 suppression are enhanced after stimulating cells with the growth factor, lysophosphatidic acid, and reduced with mTOR inhibitors, temsirolimus and INK-128. Suppression of RGS10 leads to an increase in cell proliferation, even in the presence of etoposide. In summary, the RGS10 suppression increases Rheb-GTP and mTOR signaling in ovarian cancer cells. Our results suggest that RGS10 could serve in a novel, and previously unknown, role by accelerating the hydrolysis of GTP from Rheb in ovarian cancer cells.
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
authors: Molly K
authors: MK
authors: Altman
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
authors: Ali A
authors: AA
authors: Alshamrani
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
authors: Wei
authors: W
authors: Jia
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
authors: Ha T
authors: HT
authors: Nguyen
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
authors: Jada M
authors: JM
authors: Fambrough
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
authors: Sterling K
authors: SK
authors: Tran
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
authors: Mihir B
authors: MB
authors: Patel
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
authors: Pooya
authors: P
authors: Hoseinzadeh
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
authors: Aaron M
authors: AM
authors: Beedle
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA. Electronic address: mmurph@uga.edu.
authors: Mandi M
authors: MM
authors: Murph
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; D020710:RGS Proteins; C101113:RGS10 protein, human; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins
keywords: 4E-BP1; Lysophosphatidic acid; Regulator of G protein Signaling 10 protein (RGS10); Rheb; mTOR