PMID- 25236354
OWN - NLM
STAT- MEDLINE
DCOM- 20150720
LR  - 20231213
IS  - 1600-0625 (Electronic)
IS  - 0906-6705 (Linking)
VI  - 23
IP  - 11
DP  - 2014 Nov
TI  - Knockdown of lecithin retinol acyltransferase increases all-trans retinoic acid 
      levels and restores retinoid sensitivity in malignant melanoma cells.
PG  - 832-7
LID - 10.1111/exd.12548 [doi]
AB  - Retinoids such as all-trans retinoic acid (ATRA) influence cell growth, 
      differentiation and apoptosis and may play decisive roles in tumor development 
      and progression. An essential retinoid-metabolizing enzyme known as lecithin 
      retinol acyltransferase (LRAT) is expressed in melanoma cells but not in 
      melanocytes catalysing the esterification of all-trans retinol (ATRol). In this 
      study, we show that a stable LRAT knockdown (KD) in the human melanoma cell line 
      SkMel23 leads to significantly increased levels of the substrate ATRol and 
      biologically active ATRA. LRAT KD restored cellular sensitivity to retinoids 
      analysed in cell culture assays and melanoma 3D skin models. Furthermore, 
      ATRA-induced gene regulatory mechanisms drive depletion of added ATRol in LRAT KD 
      cells. PCR analysis revealed a significant upregulation of retinoid-regulated 
      genes such as CYP26A1 and STRA6 in LRAT KD cells, suggesting their possible 
      involvement in mediating retinoid resistance in melanoma cells. In conclusion, 
      LRAT seems to be important for melanoma progression. We propose that reduction in 
      ATRol levels in melanoma cells by LRAT leads to a disturbance in cellular 
      retinoid level. Balanced LRAT expression and activity may provide protection 
      against melanoma development and progression. Pharmacological inhibition of LRAT 
      activity could be a promising strategy for overcoming retinoid insensitivity in 
      human melanoma cells.
CI  - (c) 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Amann, Philipp M
AU  - Amann PM
AD  - Department of Dermatology and Allergology, RWTH Aachen University, Aachen, 
      Germany.
FAU - Czaja, Katharina
AU  - Czaja K
FAU - Bazhin, Alexandr V
AU  - Bazhin AV
FAU - Ruhl, Ralph
AU  - Ruhl R
FAU - Skazik, Claudia
AU  - Skazik C
FAU - Heise, Ruth
AU  - Heise R
FAU - Marquardt, Yvonne
AU  - Marquardt Y
FAU - Eichmuller, Stefan B
AU  - Eichmuller SB
FAU - Merk, Hans F
AU  - Merk HF
FAU - Baron, Jens M
AU  - Baron JM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141010
PL  - Denmark
TA  - Exp Dermatol
JT  - Experimental dermatology
JID - 9301549
RN  - 11103-57-4 (Vitamin A)
RN  - 5688UTC01R (Tretinoin)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 2.3.1.- (lecithin-retinol acyltransferase)
SB  - IM
MH  - Acyltransferases/*genetics
MH  - Catalysis
MH  - Cell Line, Tumor
MH  - Cells, Cultured
MH  - Disease Progression
MH  - Gene Expression Regulation, Enzymologic
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Keratinocytes/cytology
MH  - Melanocytes/metabolism
MH  - Melanoma/*metabolism
MH  - Skin Neoplasms/*metabolism
MH  - Tretinoin/*chemistry
MH  - Vitamin A/chemistry
MH  - Melanoma, Cutaneous Malignant
OTO - NOTNLM
OT  - melanoma
OT  - retinoid resistance
OT  - retinoid sensitivity
OT  - retinoids
OT  - vitamin A metabolism
EDAT- 2014/09/23 06:00
MHDA- 2015/07/21 06:00
CRDT- 2014/09/20 06:00
PHST- 2014/09/10 00:00 [accepted]
PHST- 2014/09/20 06:00 [entrez]
PHST- 2014/09/23 06:00 [pubmed]
PHST- 2015/07/21 06:00 [medline]
AID - 10.1111/exd.12548 [doi]
PST - ppublish
SO  - Exp Dermatol. 2014 Nov;23(11):832-7. doi: 10.1111/exd.12548. Epub 2014 Oct 10.