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Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax
- Source :
- Recercat. Dipósit de la Recerca de Catalunya, instname, Dipòsit Digital de la UB, Universidad de Barcelona
- Publisher :
- Elsevier B.V.
-
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.
- Subjects :
- Indoles
Antineoplastic Agents
mTORC1
Therapeutics
Biology
Mechanistic Target of Rapamycin Complex 1
Biochemistry
mTORC2
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
Clinical trials
Protein kinases
Cell Line, Tumor
Humans
Pyrroles
Protein kinase B
Melanoma
PI3K/AKT/mTOR pathway
Pharmacology
Cell growth
Prodigiosin
TOR Serine-Threonine Kinases
RPTOR
Proteins
Ribosomal Protein S6 Kinases, 70-kDa
Terapèutica
Anti-Bacterial Agents
Gene Expression Regulation, Neoplastic
Proteïnes quinases
chemistry
Multiprotein Complexes
Cancer research
Insulin Receptor Substrate Proteins
Proto-Oncogene Proteins c-akt
Obatoclax
Transcription Factors
Assaigs clínics
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Recercat. Dipósit de la Recerca de Catalunya, instname, Dipòsit Digital de la UB, Universidad de Barcelona
- Accession number :
- edsair.doi.dedup.....f651062a85eb927b6cf228a0b1e957e8