PMID- 11020216
OWN - NLM
STAT- MEDLINE
DCOM- 20001115
LR  - 20071114
IS  - 0360-4012 (Print)
IS  - 0360-4012 (Linking)
VI  - 62
IP  - 2
DP  - 2000 Oct 15
TI  - Antisense palmitoyl protein thioesterase 1 (PPT1) treatment inhibits PPT1 
      activity and increases cell death in LA-N-5 neuroblastoma cells.
PG  - 234-40
AB  - Infantile neuronal ceroid lipofuscinosis (INCL) is a childhood neurodegenerative 
      disease caused by the selective death of cortical neurons and retinal 
      degeneration, as the result of a palmitoyl protein thioesterase 1 (PPT1) 
      deficiency. Recently, we showed that overexpression of PPT1 protects LA-N-5 human 
      neuroblastoma cells against apoptotic death (Cho and Dawson [2000a] J. Neurochem. 
      74:1478-1488) and we now show that inhibition of PPT1 increases the 
      susceptibility of these cells to apoptotic cell death. Transient transfection of 
      LA-N-5 neuroblastoma cells with PPT1-FLAG resulted in a strong expression of 
      PPT-FLAG-tagged protein as evidenced by Western blot analysis and 
      immunofluorescence. Co-transfection of a reverse-oriented (antisense) PPT1 
      (AS-PPT1) decreased the expression of PPT-FLAG to almost zero, reduced PPT1 
      enzyme activity (as measured by an in vitro assay) and increased the 
      susceptibility to apoptosis induced by C(2) ceramide. Similarly, inhibition of 
      PPT1 with a synthetic inhibitor (AcG-palmitoyl diaminoproprionate-VKIKK) (DAP1) 
      (100 microM) increased the susceptibility of the cells to apoptosis induced by 
      either C(2)-ceramide or etoposide, a common chemotherapeutic agent used in the 
      treatment of neuroblastoma. Cells stably overexpressing PPT1 were resistant to 
      apoptosis induced by DAP1 suggesting that the inhibitor has a specific action and 
      confirming that low levels of protein palmitoylation block the death pathway. 
      Drugs that raise the level of protein palmitoylation are pro-apoptotic and PPT1 
      inhibition may enhance the killing efficacy of chemotherapeutic agents used to 
      kill neuroblastoma-derived cells.
CI  - Copyright 2000 Wiley-Liss, Inc.
FAU - Cho, S
AU  - Cho S
AD  - Departments of Pediatrics, Biochemistry and Molecular Biology, University of 
      Chicago, Chicago, Illinois, USA.
FAU - Dawson, P E
AU  - Dawson PE
FAU - Dawson, G
AU  - Dawson G
LA  - eng
GR  - HD-09402/HD/NICHD NIH HHS/United States
GR  - R01 NS-36866/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Neurosci Res
JT  - Journal of neuroscience research
JID - 7600111
RN  - 0 (Antineoplastic Agents)
RN  - 0 (DNA, Antisense)
RN  - 0 (Organoplatinum Compounds)
RN  - 92784-30-0 (ARK 62-62)
RN  - EC 3.1.2.2 (Palmitoyl-CoA Hydrolase)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Death/drug effects/physiology
MH  - DNA, Antisense/*pharmacology
MH  - Humans
MH  - Neuroblastoma/metabolism
MH  - Neuronal Ceroid-Lipofuscinoses/metabolism
MH  - Organoplatinum Compounds/*pharmacology
MH  - Palmitoyl-CoA Hydrolase/biosynthesis/*drug effects/genetics
MH  - Transfection
MH  - Tumor Cells, Cultured/drug effects
EDAT- 2000/10/06 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/10/06 11:00
PHST- 2000/10/06 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/10/06 11:00 [entrez]
AID - 10.1002/1097-4547(20001015)62:2<234::AID-JNR8>3.0.CO;2-8 [pii]
AID - 10.1002/1097-4547(20001015)62:2<234::AID-JNR8>3.0.CO;2-8 [doi]
PST - ppublish
SO  - J Neurosci Res. 2000 Oct 15;62(2):234-40. doi: 
      10.1002/1097-4547(20001015)62:2<234::AID-JNR8>3.0.CO;2-8.