Fenretinide induces ubiquitin-dependent proteasomal degradation of stearoyl-CoA desaturase in human retinal pigment epithelial cells.
Fenretinide induces ubiquitin-dependent proteasomal degradation of stearoyl-CoA desaturase in human retinal pigment epithelial cells.
复制标题
DOI：
10.1002/jcp.24527
复制
发表时间：
2014-08
影响因子：
5.6
通讯作者：
Redmond, T. Michael
中科院分区：
文献类型：
--
作者：
Samuel, William;Kutty, R. Krishnan;Duncan, Todd;Vijayasarathy, Camasamudram;Kuo, Bryan C.;Chapa, Krysten M.;Redmond, T. Michael
硬脂酰辅酶A去饱和酶（Stearoyl-CoA desaturase，SCD 1）是一种内质网（endoplasmic reticulum，ER）蛋白，是单不饱和脂肪酸生物合成的限速酶，通过控制饱和脂肪酸与单不饱和脂肪酸的比例来调节细胞功能。SCD表达的增加与癌细胞的增殖和存活密切相关，而已知其减少损害增殖、诱导凋亡和恢复胰岛素敏感性。我们研究了芬维A胺（N-（4-羟基苯基）维A酰胺，4 HPR），诱导癌细胞凋亡，最近显示，提高胰岛素敏感性，是否可以调节SCD的表达。我们观察到芬维A胺降低了ARPE-19人视网膜色素上皮细胞系中的SCD蛋白和酶活性。BiP/GRP 78、ATF 4和GADD 153的表达增加涉及ER应激。衣霉素和毒胡萝卜素，已知诱导ER应激的化合物，也降低了SCD蛋白。这种降低被蛋白酶体抑制剂MG 132完全阻断。此外，PYR 41，一种泛素激活酶E1的抑制剂，阻断了芬维A胺介导的SCD降低。使用抗泛素和抗SCD抗体的免疫沉淀分析以及通过PYR 41抑制泛素化来阻断SCD损失进一步证实芬维A胺通过泛素-蛋白酶体依赖性途径介导人RPE细胞中SCD的降解。因此，芬维A胺对SCD的影响应考虑其对癌症、2型糖尿病和视网膜疾病的潜在治疗作用。
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.
登录
查看更多内容
影响因子：
3.2
作者：
Hess, Daniel;Igal, R. Ariel
通讯作者：
Igal, R. Ariel
影响因子：
4.8
作者：
Hu, Wei;Ross, Jessica;Cowart, L. Ashley
通讯作者：
Cowart, L. Ashley
影响因子：
6.2
作者：
Dillon, Roslyn;Greig, Michael J.;Bhat, B. Ganesh
通讯作者：
Bhat, B. Ganesh
影响因子：
3.3
作者：
Heinemann, FS;Ozols, J
通讯作者：
Ozols, J
影响因子：
4.8
作者：
Kraveka, Jacqueline M.;Li, Li;Bielawska, Alicja
通讯作者：
Bielawska, Alicja