Argininosuccinate synthase 1, arginine deprivation therapy and cancer management

Abstract

Metabolic reprogramming is an emerging hallmark of tumor cells. In order to survive in the nutrient-deprived environment, tumor cells rewire their metabolic phenotype to provide sufficient energy and build biomass to sustain their transformed state and promote malignant behaviors. Amino acids are the main compositions of protein, which provide key intermediate substrates for the activation of signaling pathways. Considering that cells can synthesize arginine via argininosuccinate synthase 1 (ASS1), arginine is regarded as a non-essential amino acid, making arginine depletion as a promising therapeutic strategy for ASS1-silencing tumors. In this review, we summarize the current knowledge of expression pattern of ASS1 and related signaling pathways in cancer and its potential role as a novel therapeutic target in cancer. Besides, we outline how ASS1 affects metabolic regulation and tumor progression and further discuss the role of ASS1 in arginine deprivation therapy. Finally, we review approaches to target ASS1 for cancer therapies.

Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants

“…A major causal candidate is ASS1, whose suppression in tumors limits arginine availability. 12 , 13 , 14 Although ASS1 expression level was reduced in LSCC and LUAD tumors compared with ANT, it was also reduced in many other tumors that did not show a significant R>C signal above background ( Figure 5 A, e.g., kidney, liver, brain, head and neck, and uterine cancers). This suggests that mechanisms beyond ASS1-mediated suppression of arginine production are needed to explain the presence of R>C substitutants in lung cancer specifically.…”

“…Given this compelling anti-tumor impact of arginine, it is not surprising that intracellular arginine production is suppressed in many tumors—mainly by repressing the expression of argininosuccinate synthase 1 (ASS1), a rate-limiting arginine synthetase enzyme. 12 , 13 , 14 This boosts de novo nucleotide production, 15 but also promotes arginine auxotrophy that imposes an arginine-restrictive tumor microenvironment with reduced anti-tumor activity. 11 , 16 In addition to suppressing arginine production, arginine catabolism contributes to cancer immune evasion too.…”

The Role of the L-Arginine–Nitric Oxide Molecular Pathway in Autosomal Dominant Polycystic Kidney Disease

“…ASL, which catalyzes arginine-succinate degradation in Arg and fumaric acid, is altered in arginine auxotrophic cells ( Figure 1 ). OTC, which catalyzes ornithine conversion in carbamoyl phosphate and citrulline in mitochondria, is very important in arginine recirculation [ 6 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ] ( Figure 1 ).…”

“…ASL, which catalyzes arginine-succinate degradation in Arg and fumaric acid, is altered in arginine auxotrophic cells (Figure1). OTC, which catalyzes ornithine conversion in carbamoyl phosphate and citrulline in mitochondria, is very important in arginine recirculation[6,[36][37][38][39][40][41][42] (Figure1).Due to accelerated metabolism in ADPKD, the hyperproliferative cells need high concentrations of arginine. Arginine is transported from the extracellular microenvironment in the cytoplasm by cationic amino-acid transporters (SLC7A1, SLC7A2, SLC7A3, SLC7A4, SLC3A2)[17].…”

Engineering the glioblastoma microenvironment with bioactive nanoparticles for effective immunotherapy

“…[77][78][79] Arginine promotes tumorigenesis and angiogenesis 80 and is provided by external sources since the urea cycle, the primary source of arginine, is inhibited in GBM cells through the silencing of argininosuccinate synthetase 1. 81 2.3.2 Immune cell metabolism. The tumor microenvironment alters the metabolism of immune cells.…”