未折叠蛋白反应
XBP1型
内质网
细胞生物学
蛋白激酶B
高铁F1
化学
细胞凋亡
克德尔
基因沉默
癌症研究
信号转导
热休克蛋白
热休克蛋白70
生物
生物化学
高尔基体
基因
核糖核酸
RNA剪接
作者
Simona Martinotti,Elia Ranzato,Bruno Burlando
摘要
GRP78 is a molecular chaperone of the endoplasmic reticulum (ER) that aids proper folding of nascent polypeptides. When unfolded proteins accumulate, GRP78 triggers unfolded protein response (UPR), involving activation of transcription factors like XBP1 and CHOP that may restore cell homeostasis. Increased expression of GRP78 and mild UPR can be constitutive in cancer cells, hindering apoptosis, and promoting cell survival, for example, by GRP78 relocation to the plasma membrane that activates MAPK and PI3 K/AKT pathways. These processes are thought to favor the insurgence of chemoresistance and worsen patient outcome. We have previously shown that (−)‐epigallocatechin‐3‐gallate (EGCG) enhances ROS production and alters Ca 2+ homeostasis in cell lines deriving from therapy‐recalcitrant malignant mesothelioma (MMe). We consider here the EGCG impact on GRP78 and downstream factors by using qRT‐PCR, Western blot, immunofluorescence, caspase assays, GRP78 siRNA silencing, and cell surface ELISA. MMe cells were found to display mild constitutive UPR, as shown by increased levels of GRP78, and presence of the protein at the cell surface, linked to AKT activation. Exposure to EGCG further increased GRP78 in the ER, and induced ATF4, spliced XBP1, CHOP, and EDEM expressions, combined with a reduction of cell surface GRP78 and a rise in caspase 3 and 8 activities. We propose that GRP78 accumulation in the ER, caused by EGCG, converts constitutive UPR of MMe cells into proapoptotic ER stress. This argues for a possible therapeutic use of EGCG in the treatment of MMe as a co‐drug able to abolish chemoresistance to conventional drugs at tolerable doses.
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