PMID- 22155350 OWN - NLM STAT- MEDLINE DCOM- 20120315 LR - 20211203 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 83 IP - 4 DP - 2012 Feb 15 TI - Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: prodigiosin vs. obatoclax. PG - 489-96 LID - 10.1016/j.bcp.2011.11.027 [doi] AB - 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. CI - Copyright (c) 2011 Elsevier Inc. All rights reserved. FAU - Espona-Fiedler, M AU - Espona-Fiedler M AD - Cancer Cell Biology Research Group, Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, E-08907 Barcelona, Spain. FAU - Soto-Cerrato, V AU - Soto-Cerrato V FAU - Hosseini, A AU - Hosseini A FAU - Lizcano, J M AU - Lizcano JM FAU - Guallar, V AU - Guallar V FAU - Quesada, R AU - Quesada R FAU - Gao, T AU - Gao T FAU - Perez-Tomas, R AU - Perez-Tomas R LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20111206 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Anti-Bacterial Agents) RN - 0 (Antineoplastic Agents) RN - 0 (CRTC2 protein, human) RN - 0 (IRS1 protein, human) RN - 0 (Indoles) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Multiprotein Complexes) RN - 0 (Proteins) RN - 0 (Pyrroles) RN - 0 (Transcription Factors) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1) RN - OL369FU7CJ (Prodigiosin) RN - QN4128B52A (obatoclax) SB - IM MH - Anti-Bacterial Agents/pharmacology MH - Antineoplastic Agents/pharmacology MH - Cell Line, Tumor MH - Gene Expression Regulation, Neoplastic/*drug effects MH - Humans MH - Indoles MH - Insulin Receptor Substrate Proteins/genetics/metabolism MH - Mechanistic Target of Rapamycin Complex 1 MH - Melanoma/*metabolism/pathology MH - Multiprotein Complexes MH - Phosphatidylinositol 3-Kinases/genetics/metabolism MH - Prodigiosin/*pharmacology MH - Proteins/*antagonists & inhibitors/genetics/metabolism MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - Pyrroles/*pharmacology MH - Ribosomal Protein S6 Kinases, 70-kDa/genetics/metabolism MH - TOR Serine-Threonine Kinases MH - Transcription Factors/*antagonists & inhibitors/genetics/metabolism EDAT- 2011/12/14 06:00 MHDA- 2012/03/16 06:00 CRDT- 2011/12/14 06:00 PHST- 2011/10/28 00:00 [received] PHST- 2011/11/23 00:00 [revised] PHST- 2011/11/25 00:00 [accepted] PHST- 2011/12/14 06:00 [entrez] PHST- 2011/12/14 06:00 [pubmed] PHST- 2012/03/16 06:00 [medline] AID - S0006-2952(11)00864-1 [pii] AID - 10.1016/j.bcp.2011.11.027 [doi] PST - ppublish SO - Biochem Pharmacol. 2012 Feb 15;83(4):489-96. doi: 10.1016/j.bcp.2011.11.027. Epub 2011 Dec 6.