PMID- 34033645
OWN - NLM
STAT- MEDLINE
DCOM- 20210907
LR  - 20210907
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 19
IP  - 5
DP  - 2021 May
TI  - A chemical screen for modulators of mRNA translation identifies a distinct 
      mechanism of toxicity for sphingosine kinase inhibitors.
PG  - e3001263
LID - 10.1371/journal.pbio.3001263 [doi]
LID - e3001263
AB  - We here conducted an image-based chemical screen to evaluate how medically 
      approved drugs, as well as drugs that are currently under development, influence 
      overall translation levels. None of the compounds up-regulated translation, which 
      could be due to the screen being performed in cancer cells grown in full media 
      where translation is already present at very high levels. Regarding translation 
      down-regulators, and consistent with current knowledge, inhibitors of the 
      mechanistic target of rapamycin (mTOR) signaling pathway were the most 
      represented class. In addition, we identified that inhibitors of sphingosine 
      kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. 
      Mechanistically, this is explained by an effect of the compounds on the membranes 
      of the endoplasmic reticulum (ER), which activates the integrated stress response 
      (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the 
      toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, 
      SKI-II and ABC294640, the latter in clinical trials, are also observed in cells 
      lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the 
      effects of medically used drugs on translation, identified compounds capable of 
      reducing translation independently of mTOR and has revealed that the cytotoxic 
      properties of SPHK inhibitors being developed as anticancer agents are 
      independent of SPHKs.
FAU - Corman, Alba
AU  - Corman A
AUID- ORCID: 0000-0001-8133-8967
AD  - Science for Life Laboratory, Division of Genome Biology, Department of Medical 
      Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
FAU - Kanellis, Dimitris C
AU  - Kanellis DC
AD  - Science for Life Laboratory, Division of Genome Biology, Department of Medical 
      Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
FAU - Michalska, Patrycja
AU  - Michalska P
AD  - Science for Life Laboratory, Division of Genome Biology, Department of Medical 
      Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
FAU - Haggblad, Maria
AU  - Haggblad M
AUID- ORCID: 0000-0002-3857-1437
AD  - Science for Life Laboratory, Division of Genome Biology, Department of Medical 
      Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
FAU - Lafarga, Vanesa
AU  - Lafarga V
AD  - Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), 
      Madrid, Spain.
FAU - Bartek, Jiri
AU  - Bartek J
AD  - Science for Life Laboratory, Division of Genome Biology, Department of Medical 
      Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
AD  - Danish Cancer Society Research Center, Copenhagen, Denmark.
FAU - Carreras-Puigvert, Jordi
AU  - Carreras-Puigvert J
AUID- ORCID: 0000-0002-7671-3707
AD  - Science for Life Laboratory, Division of Genome Biology, Department of Medical 
      Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
FAU - Fernandez-Capetillo, Oscar
AU  - Fernandez-Capetillo O
AUID- ORCID: 0000-0002-2690-6885
AD  - Science for Life Laboratory, Division of Genome Biology, Department of Medical 
      Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
AD  - Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), 
      Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210525
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lysophospholipids)
RN  - 0 (RNA, Messenger)
RN  - 0 (Small Molecule Libraries)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Drug Design
MH  - Enzyme Inhibitors/pharmacology
MH  - High-Throughput Screening Assays/methods
MH  - Humans
MH  - Image Processing, Computer-Assisted/methods
MH  - Lysophospholipids/metabolism
MH  - Mass Spectrometry/methods
MH  - Molecular Structure
MH  - Phosphotransferases (Alcohol Group Acceptor)/*antagonists & inhibitors/metabolism
MH  - Protein Biosynthesis/drug effects/*physiology
MH  - RNA, Messenger/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Small Molecule Libraries
MH  - Sphingosine/metabolism
PMC - PMC8183993
COIS- The authors have declared that no competing interests exist.
EDAT- 2021/05/26 06:00
MHDA- 2021/09/08 06:00
PMCR- 2021/05/25
CRDT- 2021/05/25 17:17
PHST- 2020/07/27 00:00 [received]
PHST- 2021/05/05 00:00 [accepted]
PHST- 2021/06/07 00:00 [revised]
PHST- 2021/05/26 06:00 [pubmed]
PHST- 2021/09/08 06:00 [medline]
PHST- 2021/05/25 17:17 [entrez]
PHST- 2021/05/25 00:00 [pmc-release]
AID - PBIOLOGY-D-20-02267 [pii]
AID - 10.1371/journal.pbio.3001263 [doi]
PST - epublish
SO  - PLoS Biol. 2021 May 25;19(5):e3001263. doi: 10.1371/journal.pbio.3001263. 
      eCollection 2021 May.