Fenretinide Induces Ubiquitin-Dependent Proteasomal Degradation of Stearoyl-CoA Desaturase in Human Retinal Pigment Epithelial Cells
| Autor: | William Samuel, Camasamudram Vijayasarathy, R. Krishnan Kutty, Krysten M. Chapa, Todd Duncan, T. Michael Redmond, Bryan C. Kuo |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Physiology Endoplasmic reticulum Clinical Biochemistry Cell Biology Tunicamycin Biology Cell biology chemistry.chemical_compound Endocrinology Fenretinide chemistry Ubiquitin hemic and lymphatic diseases Internal medicine MG132 Cancer cell medicine Proteasome inhibitor Unfolded protein response biology.protein medicine.drug |
| Zdroj: | Journal of Cellular Physiology. 229:1028-1038 |
| ISSN: | 0021-9541 |
| DOI: | 10.1002/jcp.24527 |
| Popis: | Stearoyl-CoA desaturase (SCD, SCD1), an endoplasmic reticulum (ER) resident protein and a rate-limiting enzyme in monounsaturated fatty acid biosynthesis, regulates cellular functions by controlling the ratio of saturated to monounsaturated fatty acids. Increase in SCD expression is strongly implicated in the proliferation and survival of cancer cells, whereas its decrease is known to impair proliferation, induce apoptosis, and restore insulin sensitivity. We examined whether fenretinide, (N-(4-hydroxyphenyl)retinamide, 4HPR), which induces apoptosis in cancer cells and recently shown to improve insulin sensitivity, can modulate the expression of SCD. We observed that fenretinide decreased SCD protein and enzymatic activity in the ARPE-19 human retinal pigment epithelial cell line. Increased expression of BiP/GRP78, ATF4, and GADD153 implicated ER stress. Tunicamycin and thapsigargin, compounds known to induce ER stress, also decreased the SCD protein. This decrease was completely blocked by the proteasome inhibitor MG132. In addition, PYR41, an inhibitor of ubiquitin activating enzyme E1, blocked the fenretinide-mediated decrease in SCD. Immunoprecipitation analysis using anti-ubiquitin and anti-SCD antibodies and the blocking of SCD loss by PYR41 inhibition of ubiquitination further corroborate that fenretinide mediates the degradation of SCD in human RPE cells via the ubiquitin–proteasome dependent pathway. Therefore, the effect of fenretinide on SCD should be considered in its potential therapeutic role against cancer, type-2 diabetes, and retinal diseases. J. Cell. Physiol. 229: 1028–1038, 2014. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. |
| Databáze: | OpenAIRE |
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