title: Thiol redox transitions in cell signaling: a lesson from N-acetylcysteine.
abstract: The functional status of cells is under the control of external stimuli affecting the function of critical proteins and eventually gene expression. Signal sensing and transduction by messengers to specific effectors operate by post-translational modification of proteins, among which thiol redox switches play a fundamental role that is just beginning to be understood. The maintenance of the redox status is, indeed, crucial for cellular homeostasis and its dysregulation towards a more oxidized intracellular environment is associated with aberrant proliferation, ultimately related to diseases such as cancer, cardiovascular disease, and diabetes. Redox transitions occur in sensitive cysteine residues of regulatory proteins relevant to signaling, their evolution to metastable disulfides accounting for the functional redox switch. N-acetylcysteine (NAC) is a thiol-containing compound that is able to interfere with redox transitions of thiols and, thus, in principle, able to modulate redox signaling. We here review the redox chemistry of NAC, then screen possible mechanisms to explain the effects observed in NAC-treated normal and cancer cells; such effects involve a modification of global gene expression, thus of functions and morphology, with a leitmotif of a switch from proliferation to terminal differentiation. The regulation of thiol redox transitions in cell signaling is, therefore, proposed as a new tool, holding promise not only for a deeper explanation of mechanisms, but indeed for innovative pharmacological interventions.
authors.affiliation: Istituto di Neurobiologia e Medicina Molecolare, CNR, Roma, Italia. tiziana.parasassi@cnr.it
authors.forename: Tiziana
authors.initials: T
authors.lastname: Parasassi
authors.forename: Roberto
authors.initials: R
authors.lastname: Brunelli
authors.forename: Graziella
authors.initials: G
authors.lastname: Costa
authors.forename: Marco
authors.initials: M
authors.lastname: De Spirito
authors.forename: Ewa
authors.initials: E
authors.lastname: Krasnowska
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundeberg
authors.forename: Eugenia
authors.initials: E
authors.lastname: Pittaluga
authors.forename: Fulvio
authors.initials: F
authors.lastname: Ursini
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D049109:Cell Proliferation; D015870:Gene Expression / Q000187:drug effects; D010084:Oxidation-Reduction; D015398:Signal Transduction; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D013438:Sulfhydryl Compounds; D019061:src-Family Kinases; D000111:Acetylcysteine