Amino Acids in Cancer and Cachexia: An Integrated View

SIMPLE SUMMARY: Cancer metabolism is an emerging field of investigation aimed at identifying cancer cell vulnerabilities in order to define novel anti-cancer therapeutic approaches based on interventions that modulate the availability of specific nutrients. Amino acids (AAs) are used by cancer cells as both building blocks for protein synthesis required for rapid tumor growth and as sources of energy. The current review aims to describe the most relevant alterations of AA metabolism that could be targeted by either AA deprivation or AA supplementation to limit tumor growth. In parallel, the reader will understand how AA availability mainly relies on and impacts cancer-host metabolism, eventually leading to a wasting paraneoplastic syndrome called cachexia. The above-mentioned AA-based interventions are here discussed also in view of their impact on the tumor host, in an attempt to provide a broader view that can improve our understanding of the patient outcome. ABSTRACT: Rapid tumor growth requires elevated biosynthetic activity, supported by metabolic rewiring occurring both intrinsically in cancer cells and extrinsically in the cancer host. The Warburg effect is one such example, burning glucose to produce a continuous flux of biomass substrates in cancer cells at the cost of energy wasting metabolic cycles in the host to maintain stable glycemia. Amino acid (AA) metabolism is profoundly altered in cancer cells, which use AAs for energy production and for supporting cell proliferation. The peculiarities in cancer AA metabolism allow the identification of specific vulnerabilities as targets of anti-cancer treatments. In the current review, specific approaches targeting AAs in terms of either deprivation or supplementation are discussed. Although based on opposed strategies, both show, in vitro and in vivo, positive effects. Any AA-targeted intervention will inevitably impact the cancer host, who frequently already has cachexia. Cancer cachexia is a wasting syndrome, also due to malnutrition, that compromises the effectiveness of anti-cancer drugs and eventually causes the patient’s death. AA deprivation may exacerbate malnutrition and cachexia, while AA supplementation may improve the nutritional status, counteract cachexia, and predispose the patient to a more effective anti-cancer treatment. Here is provided an attempt to describe the AA-based therapeutic approaches that integrate currently distant points of view on cancer-centered and host-centered research, providing a glimpse of several potential investigations that approach cachexia as a unique cancer disease.