Abstract
Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure.
Highlights
Amino acid starvation therapy has been emerging as an important treatment strategy in cancer therapy
E-box and turn on ASS1 expression [54]. These results demonstrated that ASS1 silencing and subsequent de-silencing are controlled by epigenetic mechanisms (Figure 2a,b)
We further demonstrated that the clock protein regulation of HIF-1α but up-regulated c-Myc
Summary
Amino acid starvation therapy has been emerging as an important treatment strategy in cancer therapy. The nonessential amino acids such as proline (Pro), glutamine (Gln), asparagine (Asn), and arginine (Arg) support this promise. While these amino acids can be synthesized endogenously in normal cells, many human tumors, ranging from leukemia to solid cancers, do not produce sufficient amounts of these amino acids in supporting their growth. The Pro–Gln–Asn–Arg axis represents an important nodule of cancer metabolism It occupies the major territory of amino acid metabolisms. Arg is the source of polyamine biosynthesis These results, collectively, underscore the importance of the Pro–Gln–Asn–Arg axis/loop in cancer growth and proliferation, providing a molecular basis for targeted starvation therapy.
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