Targeting Asparagine Metabolism in Solid Tumors

Abstract

Reprogramming of energy metabolism to support cellular growth is a "hallmark" of cancer, allowing cancer cells to balance the catabolic demands with the anabolic needs of producing the nucleotides, amino acids, and lipids necessary for tumor growth. Metabolic alterations, or "addiction", are promising therapeutic targets and the focus of many drug discovery programs. Asparagine metabolism has gained much attention in recent years as a novel target for cancer therapy. Asparagine is widely used in the production of other nutrients and plays an important role in cancer development. Nutritional inhibition therapy targeting asparagine has been used as an anticancer strategy and has shown success in the treatment of leukemia. However, in solid tumors, asparagine restriction alone does not provide ideal therapeutic efficacy. Tumor cells initiate reprogramming processes in response to asparagine deprivation. This review provides a comprehensive overview of asparagine metabolism in cancers. We highlight the physiological role of asparagine and current advances in improving survival and overcoming therapeutic resistance.

Keywords: asparagine metabolism; cancer; glutamine metabolism; metabolic adaptation.

Figure 1

Regulatory mechanism of ASNS expression. ASNS activity is regulated by signaling pathway in response to cellular stresses: amino acid depletion and endoplasmic reticulum (ER) stress. GCN2, general control nonderepressible 2; eIF2α, eukaryotic initiation factor 2α; ATF4, activating transcription factor 4; PERK, PKR-like endoplasmic reticulum-resident kinase.

Figure 2

Regulation of intracellular asparagine levels by ASNS, autophagy, and macropinocytosis. Cancer cells exposed to ASNase prevent cell death by inducing autophagy and macropinocytosis. Autophagy attempts to rescue cancer cells by reducing reactive oxygen species (ROS) levels through the elimination of damaged mitochondria. Cancer cells respond to asparagine depletion by inducing macropinocytosis, uptake of extracellular albumin, and amino acid degradation.