title: Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: prodigiosin vs. obatoclax.
abstract: The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modeling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.
authors.affiliation: Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, E-08907 Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Espona-Fiedler
authors.forename: V
authors.initials: V
authors.lastname: Soto-Cerrato
authors.forename: A
authors.initials: A
authors.lastname: Hosseini
authors.forename: J M
authors.initials: JM
authors.lastname: Lizcano
authors.forename: V
authors.initials: V
authors.lastname: Guallar
authors.forename: R
authors.initials: R
authors.lastname: Quesada
authors.forename: T
authors.initials: T
authors.lastname: Gao
authors.forename: R
authors.initials: R
authors.lastname: Pérez-Tomás
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011353:Prodigiosin / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D007211:Indoles; D055504:Insulin Receptor Substrate Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D011353:Prodigiosin; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C493245:CRTC2 protein, human; C526292:IRS1 protein, human; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; C520962:obatoclax