Using a biologically annotated library to analyze the anticancer mechanism of serine palmitoyl transferase (SPT) inhibitors. Issue 4 (13th February 2017)

• Record Type: Journal Article
• Authors: Sano, Osamu; Kazetani, Ken‐ichi; Adachi, Ryutaro; Kurasawa, Osamu; Kawamoto, Tomohiro; Iwata, Hidehisa
• Is Part Of: FEBS open bio. Volume 7:Issue 4(2017)
• Page Start: 495
• Page End: 503
• Publication Date: 2017-02-13
• Subjects: biologically annotated library -- combination screening -- COX‐2 -- necrosis -- serine palmitoyl transferase; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.12196
• Languages: English
• ISSNs: 2211-5463

Abstract

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. Abstract : In this study, we demonstrate that the inhibition of serine palmitoyl transferase (SPT), the rate‐limiting enzyme in sphingolipid synthesis, inhibits the growth of lung cancer cells. We also describe the mode of action analysis (MOA) of SPT inhibitors through a combination study involving a biologically annotated library and SPT inhibitors.