Abstract
Cancer cells re-program their metabolic machinery to meet the requirements of malignant transformation and progression. Glutaminase 1 (GLS1) was traditionally known as a mitochondrial enzyme that hydrolyzes glutamine into glutamate and fuels rapid proliferation of cancer cells. However, emerging evidence has now revealed that GLS1 might be a novel oncogene involved in tumorigenesis and progression of human cancers. In this study, we sought to determine whether GLS1 implicated in invasion and metastasis of colorectal carcinoma, and its underlying molecular mechanism. By analyzing a large set of clinical data from online datasets, we found that GLS1 is overexpressed in cancers compared with adjacent normal tissues, and associated with increased patient mortality. Immunohistochemical analysis of GLS1 staining showed that high GLS1 expression is significantly correlated with lymph node metastasis and advanced clinical stage in colorectal cancer patients. To investigate the underlying mechanism, we analyzed the Cancer Genome Atlas database and found that GLS1 mRNA expression is associated with a hypoxia signature, which is correlated with an increased risk of metastasis and mortality. Furthermore, reduced oxygen availability increases GLS1 mRNA and protein expression, due to transcriptional activation by hypoxia-inducible factor 1. GLS1 expression in colorectal cancer cells is required for hypoxia-induced migration and invasion in vitro and for tumor growth and metastatic colonization in vivo.
Highlights
Reprogramming of cancer cell metabolism leads to increased aerobic glycolysis (Warburg effect), which fuels the tricarboxylic acid (TCA) cycle and provides energy and biomass for rapid proliferating cells[1]
Intratumoral hypoxia increases the accumulation of hypoxiainducible factors (HIFs)-1α, which regulates multiple downstream target genes associated with cancer migration, invasion, metastasis, and relapse[10]
In the process of cancer metastasis, HIF has been shown to increase vascular permeability and promote cancer cell intravasation by inducing vascular endothelial growth factor (VEGF) activity;[24] HIFdependent expression of L1 cell adhesion molecule (L1CAM)[32], and angiopoietin-like 4 (ANGPTL4)[33] mediate breast cancer cell adherence to endothelial cells (ECs) and disruption of tight junctions between ECs, respectively; and lysyl oxidase (LOX), an extracellular enzyme that is upregulated by HIF-1, leads to collagen crosslinking and the recruitment of bone marrow-derived cells that together define the pre-metastatic niche[34]
Summary
Reprogramming of cancer cell metabolism leads to increased aerobic glycolysis (Warburg effect), which fuels the tricarboxylic acid (TCA) cycle and provides energy and biomass for rapid proliferating cells[1]. In addition to glucose metabolism, cancer cells rely on increased glutamine metabolism to maintain a functioning TCA cycle. Two genes encode glutaminase in mammalian cells: Glutaminase 1 (GLS1) is located on chromosome 2 and encodes the kidney-type isoenzyme (KGA), whereas GLS2 is located on chromosome 12 and encodes the liver-type isoform (LGA)[3]. Recent studies have reported the involvement of glutaminase in tumor cell proliferation[4], autophagy[5], signal transduction[6], and radioresistance[7]. Glutamine metabolism has been implicated in tumor metastasis[8]. Targeting glutamine metabolism by a glutamine analog (DON, 6-diazo-5-oxo-L-norleucine), which is Official journal of the Cell Death Differentiation Association
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