PMID- 34209164
OWN - NLM
STAT- MEDLINE
DCOM- 20210721
LR  - 20211204
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 13
DP  - 2021 Jun 30
TI  - The Glucosylceramide Synthase Inhibitor PDMP Causes Lysosomal Lipid Accumulation 
      and mTOR Inactivation.
LID - 10.3390/ijms22137065 [doi]
LID - 7065
AB  - For many years, the biology of glycosphingolipids was elucidated with the help of 
      glucosylceramide synthase (GCS) inhibitors such as 
      1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Additionally, PDMP 
      gained interest because of its chemosensitizing effects. Several studies have 
      successfully combined PDMP and anti-cancer drugs in the context of cancer 
      therapy. However, the mechanism of action of PDMP is not fully understood and 
      seems to go beyond glycolipid inhibition. Here, we used a functionalized 
      sphingosine analogue (pacSph) to investigate the acute effects of PDMP on 
      cellular sphingolipid distribution and found that PDMP, but not other GCS 
      inhibitors, such as ND-DNJ (also called Miglustat), induced sphingolipid 
      accumulation in lysosomes. This effect could be connected to defective export 
      from lysosome, as monitored by the prolonged lysosomal staining of sphingolipids 
      as well as by a delay in the metabolic conversion of the pacSph precursor. 
      Additionally, other lipids such as lysobisphosphatidic acid (LBPA) and 
      cholesterol were enriched in lysosomes upon PDMP treatment in a time-dependent 
      manner. We could further correlate early LBPA enrichment with dissociation of the 
      mechanistic target of rapamycin (mTOR) from lysosomes followed by nuclear 
      translocation of its downtream target, transcription factor EB (TFEB). 
      Altogether, we report here a timeline of lysosomal lipid accumulation events and 
      mTOR inactivation arising from PDMP treatment.
FAU - Hartwig, Pia
AU  - Hartwig P
AUID- ORCID: 0000-0001-9344-7714
AD  - Heidelberg University Biochemistry Center (BZH), 69120 Heidelberg, Germany.
FAU - Hoglinger, Doris
AU  - Hoglinger D
AUID- ORCID: 0000-0002-6862-0076
AD  - Heidelberg University Biochemistry Center (BZH), 69120 Heidelberg, Germany.
LA  - eng
GR  - 278001972/Deutsche Forschungsgemeinschaft/
PT  - Journal Article
DEP - 20210630
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Morpholines)
RN  - 73257-80-4 (RV 538)
RN  - EC 2.4.1.- (Glucosyltransferases)
RN  - EC 2.4.1.80 (ceramide glucosyltransferase)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Glucosyltransferases/*antagonists & inhibitors/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Lipid Metabolism/*drug effects
MH  - Lysosomes/*metabolism
MH  - Morpholines/*pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC8268262
OTO - NOTNLM
OT  - LBPA
OT  - cholesterol
OT  - clickable lipids
OT  - glycolipids
OT  - lysosomal biology
OT  - sphingolipids
COIS- The authors declare no conflict of interest.
EDAT- 2021/07/03 06:00
MHDA- 2021/07/22 06:00
PMCR- 2021/06/30
CRDT- 2021/07/02 01:37
PHST- 2021/05/07 00:00 [received]
PHST- 2021/06/24 00:00 [revised]
PHST- 2021/06/25 00:00 [accepted]
PHST- 2021/07/02 01:37 [entrez]
PHST- 2021/07/03 06:00 [pubmed]
PHST- 2021/07/22 06:00 [medline]
PHST- 2021/06/30 00:00 [pmc-release]
AID - ijms22137065 [pii]
AID - ijms-22-07065 [pii]
AID - 10.3390/ijms22137065 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Jun 30;22(13):7065. doi: 10.3390/ijms22137065.