Essential amino acid mixtures drive cancer cells to apoptosis through proteasome inhibition and autophagy activation

Cancer cells require both energy and material to survive and duplicate in a competitive environment. Nutrients, such as amino acids (AAs), are not only a caloric source, as they can modulate cell metabolism and modify hormones homeostasis. Our hypothesis is that the environmental messages provided by AAs rule the dynamics of cancer cells life or death, and the alteration of the balance between essential (EAAs) and non-essential amino acids (NEAAs) (lower and higher than 50%, respectively) present in nutrients may represent a key instrument to alter environment-dependent messages thus mastering cancer cells destiny. In this study, two amino acid mixtures, one exclusively consisting of EAAs and the other consisting of 85% essential and 15% non-essential amino acids, were tested to explore their effects on the viability of both normal and cancer cell lines and to clarify the molecular mechanisms involved. Both mixtures exerted a cell-dependent anti-proliferative, cytotoxic effect involving the inhibition of proteasome activity and the consequent activation of autophagy and apoptosis. These results, besides further validating the notion of the peculiar interdependence and extensive crosstalk between the ubiquitin-proteasome system and autophagy, indicate that variation in the ratio of EAAs and NEAAs can deeply influence cancer cell survival. Consequently, customization of dietary ratios among EAAs and NEAAs by specific amino acid mixtures may therefore represent a promising anticancer strategy able to selectively induce death of cancer cells through the induction of apoptosis via both ubiquitin-proteasome system inhibition and autophagy activation