Novel mechanism of reducing tumourigenesis: upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition.

European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)
Samy L HabibChakradhar Velagapudi

Abstract

Inhibition of mTOR by rapamycin is an important approach in cancer therapy. In early clinical trials, tuberous sclerosis complex (TSC)-related kidney tumours were found to regress following rapamycin treatment. Since loss of function of the DNA repair OGG1 enzyme has a major role in multistep carcinogenesis of the kidney and other organs, we investigated the effect of rapamycin on OGG1 regulation. Treatment of HK2 cells, mouse Tsc-deficient cells and human VHL-deficient cells (786-O) with rapamycin resulted in decrease in p70S6K phosphorylation at Thr(389), and increase in the expression of NF-YA and OGG1 proteins. In addition, rapamycin increased OGG1 promoter activity in cells transfected with OGG1 promoter construct. Furthermore, rapamycin increased the phosphorylation at Thr(172) of the energy sensor AMPK. Downregulation of AMPK phosphorylation by high glucose (HG) increases the phosphorylation of p70S6K and decreases the protein expression of NF-YA and OGG1. Pretreatment of the cells with rapamycin before exposure to HG reversed the effects of HG. However, downregulation of AMPK by dominant negative (DN)-AMPK in Tsc2(+/-) cells abolished AMPK and decreased OGG1 expression. In contrast, transfection of Tsc2(+/-) cells with ...Continue Reading

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Citations

Mar 13, 2014·Urologic Oncology·Malte BöhmOliver W Hakenberg
Aug 7, 2013·Molecular and Cellular Biology·Amaia Artal-Martinez de NarvajasDaniel D Billadeau
Jul 8, 2016·Circulation Research·Gantsetseg TumurkhuuMoshe Arditi
Jul 6, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Noor Al-ObaidiSamy L Habib
Jul 1, 2020·International Journal of Molecular Sciences·Ekaterina ProshkinaAlexey Moskalev
Jan 31, 2015·The Journal of Biological Chemistry·Suman MukhopadhyayDavid A Foster
Aug 8, 2020·Frontiers in Genetics·Thiago S MachadoMarcos R Chiaratti
Oct 19, 2020·Molecular Biology Reports·Michał SzewczukBolesław T Karwowski

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