Amino Acids in Cancer and Cachexia: An Integrated View

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.

Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells

“… 40 , 41 , 42 , 43 However, the starvation approach is problematic as it alters mitochondria function, which may be detrimental to diseased patients 43 and subsequently contributes to the cachexia-anorexia syndrome experienced by most patients with advanced cancer. 44 Other studies have attempted the use of histidine supplementation in different cancers, 30 , 45 and isoleucine supplementation in inhibiting tumor growth and angiogenesis in various cancers. 32 , 46 , 47 However, our study, to the best of our knowledge, is the first non-starvation amino acid treatment approach for pancreatic cancer, combining the use of histidine and isoleucine.…”

N‐acetyloxfenicine strongly induces mitohormesis in mice as well as in insects

“…Recent cancer research, especially on cancer cachexia, indicates the relationship between cachexia and stressrelated responses including secretion of stress-derived cytokines such as growth differentiation factor 15 (GDF15) [24] and contribution of ER stress response [25,26]. Although cancer cachexia is defined as a pathological condition characterized by progressive skeletal muscle wasting which ultimately supports tumour growth [27,28], it has been reported that oxidative stress and NO mediate muscle abnormalities [29,30]. Furthermore, decreases in SOD and catalase activities have been reported in some cachexia studies [31][32][33].…”

NNMT involving with gastric adenocarcinoma immune infiltration by driving amino acids metabolism

“…Ser/Gly metabolism promoted T cell proliferation and triggering the production of macrophage cytokines [36,38,39] . Supplementation of Gly enhances NADPH and glutathione levels, reduces ROS production, thus contributes to the expression of genes involved in in ammation and macrophage in ltration [40,41] .…”