Abstract
SummaryBackgroundSporadic clear-cell renal cell carcinoma (ccRCC) is associated with mutations in the VHL gene, upregulated mammalian target of rapamycin (mTOR) activity and glycolytic metabolism. Here, we analyze the effect of VHL mutational status on the expression level of mTOR, eIF4E-BP1, AMPK, REDD1, and PDK3 proteins.MethodsTotal proteins were isolated from 21 tumorous samples with biallelic inactivation, 10 with monoallelic inactivation and 6 tumors with a wild-type VHL (wtVHL) gene obtained from patients who underwent total nephrectomy. The expressions of target proteins were assessed using Western blot.ResultsExpressions of mTOR, eIF4EBP1 and AMPK were VHL independent. Tumors with monoallelic inactivation of VHL underexpressed REDD1 in comparison to wtVHL tumors (P = 0.042), tumors with biallelic VHL inactivation (P < 0.005) and control tissue (P = 0.004). Additionally, REDD1 expression was higher in tumors with VHL biallelic inactivation than in control tissue (P = 0.008). Only in wt tumor samples PDK3 was overexpressed in comparison to tumors with biallelic inactivation of VHL gene (P = 0.012) and controls (P = 0.016). In wtVHL ccRCC, multivariate linear regression analysis revealed that 97.4% of variability in PDK3 expression can be explained by variations in AMPK amount.ConclusionExpressions of mTOR, eIF4EBP1 and AMPK were VHL independent. We have shown for the first time VHL dependent expression of PDK3 and we provide additional evidence that VHL mutational status affects REDD1 expression in sporadic ccRCC.
Highlights
The von Hippel-Lindau tumor suppressor gene (VHL) is frequently mutated in sporadic form of clearcell renal cell carcinoma [1, 2]
We have shown for the first time VHL dependent expression of PDK3 and we provide additional evidence that VHL mutational status affects REDD1 expression in sporadic clear-cell renal cell carcinoma (ccRCC)
It is well known that mTORC1 controls cellular growth, proliferation and metabolism via its effector molecules p70S6K1 (Ribosomal protein S6 kinase beta-1) and eIF4E-BP1 (Eukaryotic Translation Initiation Factor 4E Binding Protein 1) and that it is under the control of AMPK (5’ adenosine monophosphate-activated protein kinase) and REDD1 (Regulated in Development and DNA Damage Response 1) [7,8,9,10,11,12,13,14,15]
Summary
The von Hippel-Lindau tumor suppressor gene (VHL) is frequently mutated in sporadic form of clearcell renal cell carcinoma (ccRCC) [1, 2]. Elevated activity of mammalian target of rapamycin (mTORC1/mTORC2) signaling pathways were noticed in different types of tumors including clear-cell renal carcinoma [5, 6]. It has been shown that cancer cells utilize glycolysis as the main metabolic pathway for energy production even under normoxic conditions [18,19,20]. The role of these molecules in the regulation of pyruvate dehydrogenase kinases (PDKs) is not well defined in ccRCC. Many studies were focused on the PDK1 isoform in different carcinomas, but there is no information about the expression level of PDK3 isoform in ccRCCs [21,22,23]
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