Amino acid metabolism as a therapeutic target in cancer: a review

Abstract

Malignant cells often demonstrate a proliferative advantage when compared to non-malignant cells. However, the rapid growth and metabolism required for survival can also highlight vulnerabilities specific to these malignant cells. One such vulnerability exhibited by cancer is an increased demand for amino acids (AAs), which often results in a dependency on exogenous sources of AAs or requires upregulation of de novo synthesis. These metabolic alterations can be exploited by therapy, which aims to improve treatment outcome and decrease relapse and reoccurrence. One clinically utilised strategy targeting AA dependency is the use of asparaginase in the treatment of acute lymphoblastic leukaemia (ALL), which results in a depletion of exogenous asparagine and subsequent cancer cell death. Examples of other successful strategies include the exploitation of arginine deiminase and methioninase, nutrient restriction of methionine and the inhibition of glutaminase. In this review, we summarise these treatment strategies into three promising avenues: AA restriction, enzymatic depletion and inhibition of metabolism. This review provides an insight into the complexity of metabolism in cancer, whilst highlighting these three current research avenues that have support in both preclinical and clinical settings.

Extent and Instability of Trimethylation of Histone H3 Lysine Increases With Degree of Malignancy and Methionine Addiction

“…Methionine addiction (1) is a property of all types of cancer, termed the Hoffman effect (2)(3)(4). Methionine addiction of cancer has intense current interest, especially in the rapidly expanding field of diet and cancer (5)(6)(7)(8).…”

On the illusion of auxotrophy:met15Δyeast cells can grow on inorganic sulfur thanks to the previously uncharacterized homocysteine synthase Yll058w

“…There has been a renewed interest of late in sulfur metabolism generally and more specifically in methionine metabolism, due to, among other things, the fact that methionine restriction plays a role in increasing longevity in a broad range of organisms (Green et al, 2021), and may also serve as a possible therapeutic intervention in the treatment of certain cancers (Endicott et al, 2021). There has also been a recently appreciated connection between cysteine and mitochondrial function (Hughes et al, 2020).…”

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

“…Thus, our results further validate the targeting of glutathione and glutathione synthetic pathway as a therapeutic strategy in ovarian cancer. Increased amino acid metabolism involves the overexpression of proteins associated with amino acid synthesis or their uptake in many other cancers including ovarian cancer [ 68 , 69 , 70 , 71 , 72 ]. Although such overexpression of critical proteins involved in amino acid metabolism remains to be established in HGSOC cells, our findings identify amino acid metabolism as a potential therapeutic target in ovarian cancer.…”

“…Although such overexpression of critical proteins involved in amino acid metabolism remains to be established in HGSOC cells, our findings identify amino acid metabolism as a potential therapeutic target in ovarian cancer. These results are highly significant in light of the emerging role of amino acid metabolic pathways as therapeutic targets in many cancers [ 70 , 73 , 74 ].…”