2. Academic Validation
  3. Copper Increases the Sensitivity of Cholangiocarcinoma Cells to Tripterine by Inhibiting TMX2-Mediated Unfolded Protein Reaction Activation

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

  • Adv Healthc Mater. 2023 Apr 29;e2300913. doi: 10.1002/adhm.202300913.
Hongwen Liu 1,  Lei Xu 1,  Yiyang Zhang 1,  Yiqiong Xie 2,  Lishan Wang 3,  Yue Zhou 1,  Zhangding Wang 1,  Yani Pan 1,  Wenying Li 3,  Lu Xu 2,  Xinyun Xu 4,  Ting Wang 4,  Kui Meng 4,  Jian He 5,  Yudong Qiu 6,  Guifang Xu 1 3,  Weihong Ge 2 7,  Yun Zhu 1 2 7,  Lei Wang 1 3
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, P. R. China.
  • 2 Department of Pharmacy, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 21008, P. R. China.
  • 3 Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 21008, P. R. China.
  • 4 Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, P. R. China.
  • 5 Department of Nuclear Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, P. R. China.
  • 6 Department of Hepatopancreatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, P. R. China.
  • 7 Nanjing Medical Center for Clinical Pharmacy, Nanjing, Jiangsu Province, 210008, P. R. China.
PMID: 37119498 DOI: 10.1002/adhm.202300913
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), demonstrated a significant synergistic antitumor effect on cholangiocarcinoma (CCA) cells. RNA-Seq was used to investigate the underlying mechanism, which suggests that the 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 was 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. This article is protected by copyright. All rights reserved.

Keywords

Chemotherapy resistance; Cholangiocarcinoma; Cu (II); Mitochondrial dysfunction; TMX2; Tripterine; Unfolded protein reaction.

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