Requirement of hypoxia-inducible factor 1 alpha for interleukin 1 beta induced glycolysis in colorectal cancer cells

Abstract

Colorectal cancer cells increase glycolysis to help meet the metabolic demands required for cell growth. Many factors, both endogenous and exogenous, likely drive cellular metabolism and enhance glycolytic flux in colorectal cells. Interleukin-1 beta (IL-1{beta}) is a pro-inflammatory cytokine that is elevated in colorectal cancer. In this study, we investigated the effect of IL-1{beta} toward driving the cancer cell to increase glycolysis, while also suppressing the oxidation of the fiber-derived nutrient butyrate. The results presented here demonstrate that IL-1{beta} stimulated glycolysis and inhibited maximal mitochondrial respiration. IL-1{beta} also increased the phosphorylation of AKT and hypoxia-inducible factor 1 alpha (HIF1) levels. Utilizing colorectal cancer cells with AKT1/2 or HIF1 knocked out showed the requirement of these proteins in mediating the increase in glycolysis following IL-1{beta} treatment. Importantly, AKT1/2 was identified as upstream of HIF1, as IL-1{beta} still increased phosphorylation of AKT even in the absence of HIF1. However, loss of AKT1/2 completely abolished the ability of IL-1{beta} to increase HIF1 protein levels. Tumor necrosis factor alpha (TNF), another cytokine found to be elevated in colorectal cancer, also increased glycolysis in an AKT and HIF1-dependent manner. Our data point to a common pathway through AKT activation and HIF1 upregulation, by which pro-inflammatory cytokines increase glycolysis in colorectal cancer cells to help promote cancer progression.