Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

Oncogene
M WeilerW Wick

Abstract

An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may over...Continue Reading

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Citations

Dec 25, 2013·Proceedings of the National Academy of Sciences of the United States of America·Markus WeilerWolfgang Wick
Mar 27, 2015·Neoplasia : an International Journal for Oncology Research·Hongxiang WangJuxiang Chen
Sep 23, 2014·Journal of Theoretical Biology·Giuseppina AlbanoFrancisco Torres-Ruiz
Oct 16, 2015·Neuro-oncology·Wolfgang WickFrank Winkler
Aug 19, 2015·Molecular Endocrinology·Paul T FullertonMartin M Matzuk
Jul 28, 2020·Pharmaceuticals·Angel Escamilla-RamírezCristina Trejo-Solís
Jul 5, 2019·Scientific Reports·Ammad FahimRehan Zafar Paracha
May 13, 2020·International Journal of Molecular Sciences·Maheedhara R GudaAndrew J Tsung
Oct 23, 2019·Journal of Cellular Physiology·Mei-Hua BaoHong-Shuo Sun
May 5, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Wolfgang WickMonika E Hegi

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