Abstract
BackgroundHypoxia Inducible Factors (HIF1α and HIF2α) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma. The relationship of these factors to discretely alter cell metabolic activities has largely been described in cancer cells, or in hypoxic conditions, where other confounding factors undoubtedly compete. These transcription factors and their specific roles in promoting cancer metabolic phenotypes from the earliest stages are poorly understood in pre-malignant cells.MethodsWe undertook an analysis of SV40-transformed primary kidney epithelial cells derived from newborn mice genetically engineered to express a stabilized HIF1α or HIF2α transgene. We examined the metabolic profile in relation to each gene.ResultsAlthough the cells proliferated similarly, the metabolic profile of each genotype of cell was markedly different and correlated with altered gene expression of factors influencing components of metabolic signaling. HIF1α promoted high levels of glycolysis as well as increased oxidative phosphorylation in complete media, but oxidative phosphorylation was suppressed when supplied with single carbon source media. HIF2α, in contrast, supported oxidative phosphorylation in complete media or single glucose carbon source, but these cells were not responsive to glutamine nutrient sources. This finding correlates to HIF2α-specific induction of Glul, effectively reducing glutamine utilization by limiting the glutamate pool, and knockdown of Glul allows these cells to perform oxidative phosphorylation in glutamine media.ConclusionHIF1α and HIF2α support highly divergent patterns of kidney epithelial cell metabolic phenotype. Expression of these factors ultimately alters the nutrient resource utilization and energy generation strategy in the setting of complete or limiting nutrients.
Highlights
IntroductionClear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) making up over 70% of RCC cases. ccRCC is considered to arise from cells of the renal tubule epithelium, and the majority of ccRCC cases contain inactivation of the tumor suppressor gene, von Hippel-Lindau (VHL), either by mutation or deletion [1,2]
Clear cell renal cell carcinoma is the most common subtype of renal cell carcinoma (RCC) making up over 70% of RCC cases. ccRCC is considered to arise from cells of the renal tubule epithelium, and the majority of ccRCC cases contain inactivation of the tumor suppressor gene, von Hippel-Lindau (VHL), either by mutation or deletion [1,2]
There remains an immature cell population that provides a platform for the exclusion of fibroblast cells and the promotion of epithelial cell growth by culturing the cells in serum-free media supplemented with epidermal growth factor (EGF)
Summary
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) making up over 70% of RCC cases. ccRCC is considered to arise from cells of the renal tubule epithelium, and the majority of ccRCC cases contain inactivation of the tumor suppressor gene, von Hippel-Lindau (VHL), either by mutation or deletion [1,2]. When pVHL is inactivated by mutation or deletion, HIFa subunits escape VBC mediated regulation and are stably present in the cytoplasm regardless of the oxygen state of the cell. They heterodimerize with the cognate partner, aryl hydrocarbon receptor nuclear transporter (ARNT), known as HIFb (beta). Hypoxia Inducible Factors (HIF1a and HIF2a) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma The relationship of these factors to discretely alter cell metabolic activities has largely been described in cancer cells, or in hypoxic conditions, where other confounding factors undoubtedly compete. These transcription factors and their specific roles in promoting cancer metabolic phenotypes from the earliest stages are poorly understood in pre-malignant cells
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