Altman Molly K, Alshamrani Ali A, Jia Wei, Nguyen Ha T, Fambrough Jada M, Tran Sterling K, Patel Mihir B, Hoseinzadeh Pooya, Beedle Aaron M, Murph Mandi M
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, 240 W. Green Street, Athens, GA 30602, USA.
Cancer Lett. 2015 Dec 1;369(1):175-83. doi: 10.1016/j.canlet.2015.08.012. Epub 2015 Aug 28.
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.
G蛋白信号调节因子10（RGS10）蛋白是一种GTP酶激活蛋白，可加速GTP的水解，从而经典地使G蛋白失活，最终终止信号传导。Rheb是一种小GTP酶蛋白，在其结合GDP和GTP的形式之间穿梭以激活mTOR。由于RGS10的抑制增强了卵巢癌细胞的活力，我们试图阐明其分子机制。在无血清条件下抑制RGS10后，mTOR、真核翻译起始因子4E结合蛋白1（4E-BP1）、p70S6K和核糖体蛋白S6出现磷酸化。此外，抑制RGS10会增加活化的Rheb，表明RGS10通过小G蛋白拮抗mTOR信号传导。在用生长因子溶血磷脂酸刺激细胞后，RGS10抑制的作用增强，而用mTOR抑制剂替西罗莫司和INK-128处理则作用减弱。即使在存在依托泊苷的情况下，抑制RGS10也会导致细胞增殖增加。总之，抑制RGS10会增加卵巢癌细胞中Rheb-GTP和mTOR信号传导。我们的结果表明，RGS10可能通过加速卵巢癌细胞中Rheb的GTP水解，发挥一种新的、以前未知的作用。
