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Knockdown of lecithin retinol acyltransferase increases all‐ trans retinoic acid levels and restores retinoid sensitivity in malignant melanoma cells
Author(s) -
Amann Philipp M.,
Czaja Katharina,
Bazhin Alexandr V.,
Rühl Ralph,
Skazik Claudia,
Heise Ruth,
Marquardt Yvonne,
Eichmüller Stefan B.,
Merk Hans F.,
Baron Jens M.
Publication year - 2014
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12548
Subject(s) - retinoid , gene knockdown , melanoma , retinoic acid , downregulation and upregulation , cancer research , acyltransferase , cell growth , biology , cell culture , apoptosis , chemistry , biochemistry , gene , genetics
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 ( ATR ol). 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 ATR ol 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 ATR ol in LRAT KD cells. PCR analysis revealed a significant upregulation of retinoid‐regulated genes such as CYP 26A1 and STRA 6 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 ATR ol 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.