Suppression of the GTPase-activating Protein RGS10 Increases Rheb-GTP and mTOR Signaling in Ovarian Cancer Cells

Cancer Lett. 2015 Dec 1;369(1):175-83. doi: 10.1016/j.canlet.2015.08.012. Epub 2015 Aug 28.

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.

Keywords: 4E-BP1; Lysophosphatidic acid; Regulator of G protein Signaling 10 protein (RGS10); Rheb; mTOR.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Neuropeptides
  • RGS Proteins
  • RGS10 protein, human
  • RHEB protein, human
  • Ras Homolog Enriched in Brain Protein
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Monomeric GTP-Binding Proteins