Asparagine: A Metabolite to Be Targeted in Cancers

Abstract

Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a nonessential amino acid, by L-asparaginase has been used in treating pediatric acute lymphoblastic leukemia (ALL) for decades. Of interest, unlike most solid tumor cells, ALL cells lack the ability to synthesize their own asparagine de novo effectively. However, only until recently, growing evidence suggests that solid tumor cells strive to acquire adequate amounts of asparagine to support tumor progression. This process is subjected to the regulation at various levels, including oncogenic signal, tumor-niche interaction, intratumor heterogeneity and dietary accessibility. We will review the literature on L-asparaginase-based therapy as well as recent understanding of asparagine metabolism in solid tumor progression, with the hope of shedding light into a broader cancer therapeutic strategy by perturbing its acquisition and utilization.

Amino Acid Metabolism in Cancer Drug Resistance

“…Asparagine, a nonessential amino acid, plays an important role in cancer cell proliferation, supporting cell survival under glutamine deprivation, electron transport chain inhibition, and metastasis in solid tumors [ 28 ]. Mechanistically, asparagine functions as an exchange factor for the uptake of other essential amino acids, stimulating mTORC1 signaling and nucleotide biosynthesis [ 29 , 30 ].…”

Highly Active Thermophilic L-Asparaginase from Melioribacter roseus Represents a Novel Large Group of Type II Bacterial L-Asparaginases from Chlorobi-Ignavibacteriae-Bacteroidetes Clade

“…A key player in driving the resistance to L-ASNase treatment is the expression of asparagine synthetase (ASNS), the rate-limiting enzyme for de novo biosynthesis of L-asparagine [65][66][67].…”

“…In addition to the expression of ASNS itself, studies suggest that the availability of aspartate and glutamine, two indispensable substrates of ASNS, are also important for the cellular adaptation to the depletion of exogenous asparagine [67,68]. In cell culture conditions, most cancer cells can use glutamine to synthesize aspartate de novo.…”

Mitochondrial Effects on Seeds of Cancer Survival in Leukemia

“…Tucci et al (40) clarified that ALL cells accelerate adipocyte lipolysis and use the produced FFA to complement lipogenesis and de novo proliferation. In another study, Chronic Lymphocytic Leukemia (CLL) cells, in comparison with normal B lymphocytes, are able to catabolize lipids that allows usage of FFAs for oxidative respiration (41). FFAs also can interact with the nuclear receptor peroxisome proliferator-activated receptor a (PPARa).…”

“…Orgel et al (43) showed that glutamine secreted by adipocytes protects leukemia cells from treatment with L-asparaginase. This is especially true, considering that L-asparaginase is used in the treatment of ALL, because leukemic lymphoblasts are quite sensitive to exogenous asparagine and glutamine depletion (41,43).…”