title: Essential amino acid mixtures drive cancer cells to apoptosis through proteasome inhibition and autophagy activation.
abstract: 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, but can also modulate cell metabolism and modify hormone homeostasis. Our hypothesis is that the environmental messages provided by AAs rule the dynamics of cancer cell life or death, and the alteration of the balance between essential amino acids (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 AA mixtures, one exclusively consisting of EAAs and the other consisting of 85% EAAs and 15% NEAAs, 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 (UPS) 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 AA mixtures may represent a promising anticancer strategy able to selectively induce death of cancer cells through the induction of apoptosis via both UPS inhibition and autophagy activation.
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonfili
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecarini
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cuccioloni
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Angeletti
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Flati
authors.affiliation: Human Anatomy and Physiopathology Unit, Department of Clinical and Experimental Sciences, School of Medicine, University of Brescia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Corsetti
authors.affiliation: Cardiac Rehabilitation Division, Istituti Clinici Scientifici Maugeri, IRCCS Lumezzane, Lumezzane, Italy.
authors.forename: Evasio
authors.initials: E
authors.lastname: Pasini
authors.affiliation: Department of Clinical Sciences and Community Health, State University of Milan, Italy.
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Dioguardi
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Eleuteri
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000601:Amino Acids, Essential / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001940:Breast / Q000166:cytology; D018938:Caco-2 Cells / Q000187:drug effects / Q000201:enzymology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D045325:HCT116 Cells / Q000187:drug effects* / Q000201:enzymology; D006367:HeLa Cells / Q000187:drug effects* / Q000201:enzymology; D056945:Hep G2 Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D061988:Proteasome Inhibitors / Q000494:pharmacology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000601:Amino Acids, Essential; D061988:Proteasome Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D046988:Proteasome Endopeptidase Complex
keywords: amino acids; apoptosis; autophagy; cancer; proteasome