A genome-wide screen for FTY720-sensitive mutants reveals genes required for ROS homeostasis

Authors:

Kanako Hagihara1, Kanako Kinoshita1, Kouki Ishida1, Shihomi Hojo1, Yoshinori Kameoka1, Ryosuke Satoh1, Teruaki Takasaki1 and Reiko Sugiura1

doi: 10.15698/mic2017.12.601
Volume 4, pp. 390 to 401, published 27/11/2017.

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Affiliations:

1 Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka City, Osaka 577-8502, Japan.

Keywords: 

FTY720, ROS, chemical genomics, fission yeast, mechanism of cell death.

Corresponding Author(s):

Reiko Sugiura, Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka City, Osaka 577-8502, Japan; sugiurar@phar.kindai.ac.jp

Conflict of interest statement:

The authors declare no conflict of interest.

Please cite this article as:

Kanako Hagihara, Kanako Kinoshita, Kouki Ishida, Shihomi Hojo, Yoshinori Kameoka, Ryosuke Satoh, Teruaki Takasaki and Reiko Sugiura (2017). A genome-wide screen for FTY720-sensitive mutants reveals genes required for ROS homeostasis. Microbial Cell 4(12): 390-401. doi: 10.15698/mic2017.12.601

© 2017 Hagihara et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

Fingolimod hydrochloride (FTY720), a sphingosine-1-phosphate (S1P) analogue, is an approved immune modulator for the treatment of multiple sclerosis (MS). Notably, in addition to its well-known mode of action as an S1P modulator, accumulating evidence suggests that FTY720 induces apoptosis in various cancer cells via reactive oxygen species (ROS) generation. Although the involvement of multiple signaling molecules, such as JNK (Jun N-terminal kinase), Akt (alpha serine/threonine-protein kinase) and Sphk has been reported, the exact mechanisms how FTY720 induces cell growth inhibition and the functional relationship between FTY720 and these signaling pathways remain elusive. Our previous reports using the fission yeast Schizosaccharomyces pombe as a model system to elucidate FTY720-mediated signaling pathways revealed that FTY720 induces an increase in intracellular Ca2+ concentrations and ROS generation, which resulted in the activation of the transcriptional responses downstream of Ca2+/calcineurin signaling and stress-activated MAPK signaling, respectively. Here, we performed a genome-wide screening for genes whose deletion induces FTY720-sensitive growth in S. pombe and identified 49 genes. These gene products are related to the biological processes involved in metabolic processes, transport, transcription, translation, chromatin organization, cytoskeleton organization and intracellular signal transduction. Notably, most of the FTY720-sensitive deletion cells exhibited NAC-remedial FTY720 sensitivities and dysregulated ROS homeostasis. Our results revealed a novel gene network involving ROS homeostasis and the possible mechanisms of the FTY720 toxicity.