Warburg effect regulated by amphiregulin in the development of colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality worldwide. Amphiregulin (AREG), a member of the epidermal growth factor family and a rational target for CRC therapy, is essential for the three-dimensional structure of tumor formation. To clone the genes associated with increased AREG expression, we performed a cDNA microarray analysis in two CRC cell lines undergoing two-dimensional (2DC) and three-dimensional culture (3DC). Upregulated (>2.0-fold) and downregulated (<0.5-fold) genes in 3DC compared with 2DC were selected. Pathway analysis using DAVID based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases revealed a number of genes involved in glycolysis. In CRC cells, glucose elevated the expression of GLUT1 and AREG as well as the activity of the hypoxia-inducible factor 1 (HIF-1) luciferase reporter promoter. The suppression of AREG expression reduced the uptake of glucose and production of lactate. Luciferase assay identified a critical regulatory region for AREG expression between −130 and −180 bp upstream of the start site, which contained a carbohydrate response element (ChoRE). Max-like protein X (MLX) bound to ChoRE and enhanced the expression of AREG. Together these data suggest that AREG plays a pivotal role in the development of CRC through activation of the Warburg effect.

The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

“…We therefore propose that the glucose-sensing transcription factor MLX and myokine signaling may encompass a novel part of the molecular pathway necessary for glucose-induced adaptive myogenesis. Given its widespread expression, MLX may modulate the transcription of secreted signaling proteins in response to glucose in many cell types, which was also implicated by a recent study in colorectal cancer cells (Nam et al 2015). Therefore, our study indicates that MLX has more diverse roles than previously anticipated, presumably in concert with the large network of positive and negative transcriptional regulatory factors to which it belongs .…”

ADAM17 is essential for ectodomain shedding of the EGF‐receptor ligand amphiregulin

“…Amphiregulin plays an important role in pathological processes, including psoriasis induction , cancer progression, and resistance to chemotherapy and anti‐EGFR therapies . For example, AREG has been characterized as a multicrine – autocrine, paracrine, and endocrine (systemic) – growth factor in primary and metastatic epithelial cancers .…”

“…Results of in vivo studies implicate ADAM17 as the specific metalloprotease contributing to the ectodomain shedding of AREG , a potent growth factor implicated in proliferative skin diseases, and primary and metastatic epithelial cancers . Moreover, results of in vitro studies have suggested ADAM17 as a key sheddase ; nevertheless, ADAM8‐, ADAM15‐, and batimastat (broad metalloprotease inhibitor)‐sensitive metalloproteases have also been implicated in AREG shedding in vitro .…”

Hypoxia inducible factor-1α: Its role in colorectal carcinogenesis and metastasis

“…In CRC cells, the FIH-1 expression markedly decreased HIF1α mediated expression of GLUT1 and VEGF. The expression of GLUT1 in CRC was partly regulated by the Amphiregulin-EGFR pathway [31]. Amphiregulin may possibly transactivate EGFR and consequently induce HIF-1α, leading to tumor progression and activation of genes responsible for the Warburg effect [31].…”