title: Phosphorylation-independent mTORC1 inhibition by the autophagy inducer Rottlerin.
abstract: We recently found that Rottlerin not only inhibits proliferation but also causes Bcl-2- and Beclin 1-independent autophagic death in apoptosis-resistant breast adenocarcinoma MCF-7 cells. Having excluded a role for canonical signaling pathways, the current study was aimed to investigate the contribution of the AMPK/mTOR axis in autophagy induction and to search for the upstream signaling molecules potentially targeted by Rottlerin. Using several enzyme inhibitors, Western blotting analysis, mTOR siRNA and pull down assay, we demonstrate that the Rottlerin-triggered autophagy is mediated by inhibition of mTORC1 activity through a novel AMPK and mTORC1 phosphorylation-independent mechanism, likely mediated by the direct interaction between Rottlerin and mTOR.
authors: Department of Life Sciences, University of Siena, via Aldo Moro, Siena 7-53100, Italy.
authors: C
authors: C
authors: Torricelli
authors: Department of Life Sciences, University of Siena, via Aldo Moro, Siena 7-53100, Italy.
authors: E
authors: E
authors: Daveri
authors: Department of Life Sciences, University of Siena, via Aldo Moro, Siena 7-53100, Italy.
authors: S
authors: S
authors: Salvadori
authors: Department of Biology and Evolution, University of Ferrara, Via Luigi Borsari 46, Ferrara 44100, Italy; Department of Food and Nutrition, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: G
authors: G
authors: Valacchi
authors: Department of Life Sciences, University of Siena, via Aldo Moro, Siena 7-53100, Italy.
authors: F
authors: F
authors: Ietta
authors: Department of Medicine, surgery and neuroscience, University of Siena, Strada delle Scotte, Siena 4-53100, Italy.
authors: M
authors: M
authors: Muscettola
authors: Department of Medical biotechnologies, University of Siena, Strada delle Scotte, Siena 4-53100, Italy.
authors: F
authors: F
authors: Carlucci
authors: Department of Life Sciences, University of Siena, via Aldo Moro, Siena 7-53100, Italy. Electronic address: emanuela.maioli@unisi.it.
authors: E
authors: E
authors: Maioli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000098:Acetophenones / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; D001578:Benzopyrans; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; C085746:rottlerin; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Autophagy; Raptor; Rottlerin; mTOR