title: N-Formyl-3,4-methylenedioxy-benzylidene-gamma-butyrolaetam, KNK437 induces caspase-3 activation through inhibition of mTORC1 activity in Cos-1 cells.
abstract: The mammalian target of rapamycin complex 1 (mTORC1: mTOR-raptor interaction) and heat shock protein 70 (Hsp70) regulate various cellular processes and are crucial for the progression of many cancers and metabolic diseases. In the recent study, we reported that interaction of Hsp70 with tuberous sclerosis complex 1 (TSC1) regulated apoptosis. This study was designed to elucidate the underlying mechanism in Cos-1 cells. Here, we show that N-formyl-3,4-methylenedioxy-benzylidene-gamma-butyrolaetam (KNK437), which inhibits the expression level of Hsp70, abrogated phosphorylation of mTOR and S6K in response to insulin, and inhibited mTORC1 activity via disruption of an interaction between mTOR and raptor. In addition, KNK437 did not alter TSC1/2 complex formation. Furthermore, KNK437 inhibited the mTOR-raptor interaction on the outer membrane of the mitochondria and triggered caspase-3 activation. A reduction in the level of Hsp70 could result in the inhibition of the mTORC1 signaling pathway, thereby inducing apoptosis.
authors.affiliation: Department of Applied Biology and Chemistry, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Inoue
authors.forename: Takumi
authors.initials: T
authors.lastname: Uyama
authors.forename: Junko
authors.initials: J
authors.lastname: Hayashi
authors.forename: Akito
authors.initials: A
authors.lastname: Watanabe
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Tadokoro
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D019556:COS Cells; D053148:Caspase 3 / Q000096:biosynthesis*; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D000076223:Regulatory-Associated Protein of mTOR; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001559:Benzhydryl Compounds; D047908:Intracellular Signaling Peptides and Proteins; C410027:KNK 437; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011760:Pyrrolidinones; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; C000624650:TSC1 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3