2. Academic Validation
  3. ROS confer resistance to 3TC in p53 mutant colorectal cancer by promoting autophagy and ER stress

ROS confer resistance to 3TC in p53 mutant colorectal cancer by promoting autophagy and ER stress

  • Eur J Pharmacol. 2025 Sep 5:1002:177837. doi: 10.1016/j.ejphar.2025.177837.
Yiting Lu 1,  Ying Jiang 2,  Xinyu Liao 2,  Junqi Xiang 2,  Xiaohui Xu 2,  Yidan Han 2,  Lin Cui 2,  Jian Zhang 2,  Yue Li 2,  Xia Zhang 2,  Yunlong Lei 3,  Longhao Li 4
Affiliations

Affiliations

  • 1 Department of Oncology, Laboratory of Immunity, Inflammation & Cancer, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; General Surgery Department, Chongqing General Hospital, School of Medicine, Chongqing University, Chongqing, 401147, China.
  • 2 Department of Oncology, Laboratory of Immunity, Inflammation & Cancer, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 3 Department of Biochemistry and Molecular Biology, and Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China; Tianfu Jincheng Laboratory, Chengdu, 610093, China. Electronic address: leiyunglong@cqmu.edu.cn.
  • 4 Department of Oncology, Laboratory of Immunity, Inflammation & Cancer, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: llh@hospital.cqmu.edu.cn.
PMID: 40517882 DOI: 10.1016/j.ejphar.2025.177837
Abstract

Colorectal Cancer (CRC) is among the most frequently diagnosed cancers globally. Lamivudine (3 TC), a nucleoside Reverse Transcriptase Inhibitor (NRTI) commonly used for treating Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV), has recently demonstrated Anticancer activity against p53-mutant CRC in Phase 2 clinical trials. However, the underlying mechanisms remain elusive. Our study revealed that 3 TC promotes the accumulation of Reactive Oxygen Species (ROS), which potentially counters its Anticancer efficacy in p53-mutant CRC cells. Furthermore, we observed that ROS induced by 3 TC stimulates Autophagy independently of the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway and also activates the activating transcription factor 4 (ATF4)-mediated endoplasmic reticulum (ER) stress pathway. By inhibiting Autophagy and ER stress, the Anticancer effect of 3 TC was enhanced. In summary, our findings demonstrate that ROS accumulation attenuates the Anticancer efficacy of 3 TC by promoting Autophagy and ER stress, providing novel insights into the molecular mechanisms underlying 3 TC's therapeutic role in p53-mutant CRC.

Keywords

3 TC; Autophagy; Colorectal cancer; ER stress; ROS.

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