Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells.

Altman MK, Alshamrani AA, Jia W, Nguyen HT, Fambrough JM, Tran SK, Patel MB, Hoseinzadeh P, Beedle AM, Murph MM
Cancer Lett. 2015 369 (1): 175-83

PMID: 26319900 · PMCID: PMC4654121 · DOI:10.1016/j.canlet.2015.08.012

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.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

MeSH Terms (13)

Cell Line, Tumor Cell Survival Female Humans Monomeric GTP-Binding Proteins Neuropeptides Ovarian Neoplasms Phosphorylation Protein Processing, Post-Translational Ras Homolog Enriched in Brain Protein RGS Proteins Signal Transduction TOR Serine-Threonine Kinases

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