Novel mechanism of reducing tumourigenesis

Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition

Samy L Habib, Balakuntalam S Kasinath, Ruth Rector Arya, Sandra Vexler, Chakradhar Velagapudi

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 Thr389, 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 Thr172 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 DN-S6K abolished p70S6K phosphorylation and increased OGG1 expression, a response enhanced by rapamycin. Treatment of Tsc2+/- mice with rapamycin resulted in activation of AMPK, downregulation of phospho-p70S6K and enhanced OGG1 expression. Our data show that inhibition of mTOR can activate AMPK and lead to upregulation of DNA repair enzyme OGG1. These data comprise the first report to provide one mechanism whereby rapamycin might prevent or inhibit the formation and progression of certain cancers.

Original languageEnglish (US)
Pages (from-to)2806-2820
Number of pages15
JournalEuropean Journal of Cancer
Volume46
Issue number15
DOIs
StatePublished - Oct 2010

Fingerprint

DNA Repair Enzymes
AMP-Activated Protein Kinases
Sirolimus
Up-Regulation
70-kDa Ribosomal Protein S6 Kinases
Phosphorylation
Down-Regulation
Glucose
Kidney
Neoplasms
Tuberous Sclerosis
Transfection
Carcinogenesis
Proteins
Clinical Trials

Keywords

  • AMPK
  • NF-YA
  • OGG1
  • p70S6K
  • Rapamycin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Novel mechanism of reducing tumourigenesis : Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition. / Habib, Samy L; Kasinath, Balakuntalam S; Arya, Ruth Rector; Vexler, Sandra; Velagapudi, Chakradhar.

In: European Journal of Cancer, Vol. 46, No. 15, 10.2010, p. 2806-2820.

Research output: Contribution to journalArticle

Habib, Samy L ; Kasinath, Balakuntalam S ; Arya, Ruth Rector ; Vexler, Sandra ; Velagapudi, Chakradhar. / Novel mechanism of reducing tumourigenesis : Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition. In: European Journal of Cancer. 2010 ; Vol. 46, No. 15. pp. 2806-2820.
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