Copper Increases the Sensitivity of Cholangiocarcinoma Cells to Tripterine by Inhibiting TMX2‐Mediated Unfolded Protein Reaction Activation

Abstract

Chemotherapy‐induced adaptive resistance is a significant factor that contributes to low therapeutic efficacy in tumor cells. The unfolded protein response (UPR) is a key mechanism in the development of drug resistance and serves as a critical reactive system for endoplasmic reticulum stress. Cu(II) can reduce the abundance of 60S ribosomal subunits and inhibit rRNA processing, leading to a decrease in the translation efficiency of the GRP78/BiP mRNA, which serves as a primary sensor for UPR activation. In this study, CuET‐Lipid@Cela, composed of CuET and tripterine (Cela), demonstrates a significant synergistic antitumor effect on cholangiocarcinoma (CCA) cells. RNA‐Seq is used to investigate the underlying mechanism, which suggests that the transmembrane protein 2 (TMX2) gene may be crucial in Cu(II) regulation of UPR by inhibiting the activation of GRP78/BiP and PERK/eIF2α. The synergistic antitumor efficacy of CuET‐Lipid@Cela via inhibition of TMX2 is also confirmed in a myrAKT/YapS127A plasmid‐induced primary CCA mouse model, providing new insights into the reversal of acquired chemotherapy‐induced resistance in CCA.

Alleviating Pyroptosis of Intestinal Epithelial Cells to Restore Mucosal Integrity in Ulcerative Colitis by Targeting Delivery of 4-Octyl-Itaconate

“…4-OI/BLipo was prepared using the ethanol injection method . In brief, a mixture of lecithin, cholesterol, DSPE-PEG 2000 , butyrate, and 4-OI, in a ratio of 100:25:60:50:10, was dissolved in anhydrous ethanol.…”

TMX family genes and their association with prognosis, immune infiltration, and chemotherapy in human pan-cancer

“…It means that the expression of the TMX family genes have an obvious intratumoral heterogeneity. TMX2 interference attenuates mitochondrial respiration, leading to enhanced aerobic glycolysis, which promotes tumor cell growth [ 16 ]. Although the roles of TMX family genes in cancer is increasingly discovered, their biological roles in tumor immune response and the association of their expression with immunotherapy drug resistance are seldom reported.…”