Novel mechanism of reducing tumourigenesis: Upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition
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 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.
Available from: Malte Boehm
- "The significance of the pathway phosphatidylinositol-3- kinase/Akt/mammalian target of rapamycin (mTOR)   and of the pathway mTOR/AMPK/OGG1  in the oncogenesis of urothelial carcinomas have been elucidated. Staining of molecules of the mTOR pathway and of hypoxia-inducible factor could become relevant for personalized medicine , as medication interacting with this pathway is available. "
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ABSTRACT: Urine cytology is considered a valid diagnostic method of urological and nephrological diagnosis and follow-up, whereas immunohistochemistry is an indispensable adjunct to histopathology. The combination of both—urinary immunocytology—has, so far, only attained a marginal role. This review gives a state-of-the-art update of urinary markers and relevant epitopes, elucidates some methodological pitfalls, and gives an outlook on the promise of urinary immunocytology today. It suggests that morphological urine cytology should be amended by immunology in a mutual quest of urologists and pathologists to improve the diagnostic power of urine cytology. The cost-effectiveness of the method is considered. This review also sheds light on the age-old dispute among pathologists about the nature of urothelial carcinoma that is reflected in the frequent and controversial reclassifications of the disease.
Urologic Oncology 05/2014; 32(4). DOI:10.1016/j.urolonc.2013.11.002 · 2.77 Impact Factor
Available from: Samy Lewiz Habib
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ABSTRACT: The tuberous sclerosis complex (TSC) is caused by mutation in either of 2 tumor suppressor genes, TSC-1 (encodes hamartin) and TSC-2 (encodes tuberin). In humans, deficiency in TSC1/2 is associated with benign tumors in many organs, including renal angiomyolipoma (AML) but rarely renal cell carcinoma (RCC). In contrast, deficiency of TSC function in the Eker rat is associated with RCC. Here, we have investigated the activity of PI 3-K and the expression of PTEN, p53, tuberin, p-mTOR, and p-p70S6K in both Eker rat RCC and human renal AML. Compared to normal tissue, increased PI 3-K activity was detected in RCC of Eker rats but not in human AML tissue. In contrast, PTEN was highly expressed in AML but significantly reduced in the renal tumors of Eker rats. Phosphorylation on Ser(2448) of mTOR and Thr(389) of p70S6K were significantly increased in both RCC and AML compared to matching control tissue. Total tuberin was significantly decreased in AML while completely lost in RCC of Eker rats. Our data also show that while p53 protein expression is lost in rat RCC, it was highly elevated in AML. These novel data provide evidence that loss of TSC-2, PTEN, and p53 as well as activation of PI 3-K and mTOR is associated with kidney cancer in the Eker rat, while sustained expression of TSC-2, PTEN, and p53 may prevent progression of kidney cancer in TSC patients.
Genes & cancer 11/2011; 2(11):1051-60. DOI:10.1177/1947601912445376
Available from: PubMed Central
Oncotarget 12/2011; 2(12):958-9. DOI:10.18632/oncotarget.381 · 6.36 Impact Factor
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