Compound C prevents the unfolded protein response during glucose deprivation through a mechanism independent of AMPK and BMP signaling.

Inhibiting the unfolded protein response (UPR) can be a therapeutic approach, especially for targeting the tumor microenvironment. We found that compound C (also known as dorsomorphin) prevented the UPR and exerted enhanced cytotoxicity during glucose deprivation. The UPR-inhibiting activity of compound C was not associated with either AMPK or BMP signaling inhibition. To induce the UPR, we treated HT1080 cells for 18 hours under ER stress conditions by adding 10 mM 2-Deoxy-D-glucose (2DG) to culture medium. UPR inhibitors (compound C, versipelostatin and phenformin) were added just before 2DG was added in medium. Total 8 samples were prepared for RNA extraction and hybridization on Affymetrix microarrays.

抑制未折叠蛋白反应（unfolded protein response, UPR）可作为一类治疗策略，尤其可用于靶向肿瘤微环境。本研究发现，化合物C（又名 dorsomorphin）能够阻断未折叠蛋白反应，并在葡萄糖剥夺条件下增强细胞毒性效应。化合物C的未折叠蛋白抑制活性与腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）及骨形态发生蛋白（Bone Morphogenetic Protein, BMP）信号通路的抑制均无相关性。为诱导未折叠蛋白反应，我们向培养基中添加10 mM 2-脱氧葡萄糖（2-Deoxy-D-glucose, 2DG），将HT1080细胞置于内质网应激（endoplasmic reticulum stress, ER stress）环境中培养18小时。在培养基中添加2DG之前，先加入未折叠蛋白反应抑制剂（化合物C、维司比洛司他汀（versipelostatin）和苯乙双胍（phenformin））。本研究共计制备8份样本，用于RNA提取及Affymetrix基因芯片杂交实验。