Arginine dependence of tumor cells: targeting a chink in cancer’s armor

Abstract

Arginine, one among the 20 most common natural amino acids, has a pivotal role in cellular physiology as it is being involved in numerous cellular metabolic and signaling pathways. Dependence on arginine is diverse for both tumor and normal cells. Because of decreased expression of argininosuccinate synthetase and/or ornithine transcarbamoylase, several types of tumor are auxotrophic for arginine. Deprivation of arginine exploits a significant vulnerability of these tumor cells and leads to their rapid demise. Hence, enzyme-mediated arginine depletion is a potential strategy for the selective destruction of tumor cells. Arginase, arginine deiminase and arginine decarboxylase are potential enzymes that may be used for arginine deprivation therapy. These arginine catabolizing enzymes not only reduce tumor growth but also make them susceptible to concomitantly administered anti-cancer therapeutics. Most of these enzymes are currently under clinical investigations and if successful will potentially be advanced as anti-cancer modalities.

Raman spectroscopy for accurately characterizing biomolecular changes in androgen‐independent prostate cancer cells

“…Abnormalities in arginine metabolism enzymes have been observed in several types of tumours and those cancers support biological processes by relying on extracellular arginine. Therefore, arginine deprivation is currently being investigated as a novel cancer therapy . As such, the present work has shown the potential of Raman spectroscopy not only as diagnostic technique, but also to detect biomolecular changes in androgen‐independent prostate cancer cells that could help in establishing novel treatment approaches.…”

Time-resolved analysis of amino acid stress identifies eIF2 phosphorylation as necessary to inhibit mTORC1 activity in liver

“…Our study identifies GCN2 and its downstream effector eIF2 as essential components that coordinate hepatic mTORC1 during amino acid stress. These data complement and provide mechanistic insight as to why maladaptive activation of hepatic mTORC1 in Gcn2 -/-mice associates with greater morbidity and metabolic toxicity (8) and have important implications for the clinical use of rapidly growing class of GCN2-activating drugs (35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Gcn2 is not an essential gene and so far is found to have 594 missense, 28 nonsense, and 33 frame-shifting mutations in the human population (45).…”

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

“…Such effects were seen in the human cervical epithelial carcinoma cell line HeLa. Mechanistically, ADC treatment causes cell cycle arrest and apoptosis [51][52][53]. Although these data suggest that ADC may provide another interesting agent for Arg-depleting strategies, there are major drawbacks of this enzyme.…”