title: The Enigma of Rapamycin Dosage.
abstract: The mTOR pathway is a critical regulator of cell growth, proliferation, metabolism, and survival. Dysregulation of mTOR signaling has been observed in most cancers and, thus, the mTOR pathway has been extensively studied for therapeutic intervention. Rapamycin is a natural product that inhibits mTOR with high specificity. However, its efficacy varies by dose in several contexts. First, different doses of rapamycin are needed to suppress mTOR in different cell lines; second, different doses of rapamycin are needed to suppress the phosphorylation of different mTOR substrates; and third, there is a differential sensitivity of the two mTOR complexes mTORC1 and mTORC2 to rapamycin. Intriguingly, the enigmatic properties of rapamycin dosage can be explained in large part by the competition between rapamycin and phosphatidic acid (PA) for mTOR. Rapamycin and PA have opposite effects on mTOR whereby rapamycin destabilizes and PA stabilizes both mTOR complexes. In this review, we discuss the properties of rapamycin dosage in the context of anticancer therapeutics.
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, New York.
authors.forename: Suman
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, New York.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Frias
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, New York.
authors.forename: Amrita
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Molecular Pharmacology & Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Paige
authors.initials: P
authors.lastname: Yellen
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, New York. Department of Pharmacology, Weill-Cornell Medical College, New York, New York. foster@genectr.hunter.cuny.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Foster
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus