title: Using a biologically annotated library to analyze the anticancer mechanism of serine palmitoyl transferase (SPT) inhibitors.
abstract: Mechanistic understanding is crucial to anticancer drug discovery. Here, we reveal that inhibition of serine palmitoyl transferase (SPT), the rate-limiting enzyme in sphingolipid synthesis, induced death in a lung cancer cell line via a necrosis-dependent pathway. To elucidate the mechanism of cell death induced by SPT inhibition, a biologically annotated library of diverse compounds was screened with an SPT inhibitor. This analysis identified suppressors of SPT inhibitor-mediated cell death. Further analysis using hit compounds from this screening revealed that SPT inhibitors induce COX-2 expression, leading to necrosis-dependent cell death. SPT inhibitors might therefore represent novel candidates for cancer therapy via necrosis pathway regulation. Our data illustrate that compound combination screening of biologically annotated libraries could be used for mechanistic elucidation.
authors.affiliation: BioMolecular Research Laboratories, Research Takeda Pharmaceutical Company Ltd. Fujisawa Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sano
authors.affiliation: BioMolecular Research Laboratories, Research Takeda Pharmaceutical Company Ltd. Fujisawa Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Kazetani
authors.affiliation: BioMolecular Research Laboratories, Research Takeda Pharmaceutical Company Ltd. Fujisawa Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Adachi
authors.affiliation: Oncology Drug Discovery Unit, Research Takeda Pharmaceutical Company Ltd. Fujisawa Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kurasawa
authors.affiliation: BioMolecular Research Laboratories, Research Takeda Pharmaceutical Company Ltd. Fujisawa Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: BioMolecular Research Laboratories, Research Takeda Pharmaceutical Company Ltd. Fujisawa Japan.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Iwata
keywords: COX‐2; biologically annotated library; combination screening; necrosis; serine palmitoyl transferase