TXN inhibitor impedes radioresistance of colorectal cancer cells with decreased ALDH1L2 expression via TXN/NF-κB signaling pathway.

Abstract

BACKGROUND:

Colorectal cancer (CRC) is prevalent worldwide and is often challenged by treatment failure and recurrence due to resistance to radiotherapy. Here, we aimed to identify the elusive underlying molecular mechanisms of radioresistance in CRC.

METHODS:

Weighted gene co-expression network analysis was used to identify potential radiation-related genes. Colony formation and comet assays and multi-target single-hit survival and xenograft animal models were used to validate the results obtained from the bioinformatic analysis. Immunohistochemistry was performed to examine the clinical characteristics of ALDH1L2. Co-immunoprecipitation, immunofluorescence and flow cytometry were used to understand the molecular mechanisms underlying radioresistance.

RESULTS:

Bioinformatic analysis, in vitro, and in vivo experiments revealed that ALDH1L2 is a radiation-related gene, and a decrease in its expression induces radioresistance in CRC cells by inhibiting ROS-mediated apoptosis. Patients with low ALDH1L2 expression exhibit resistance to radiotherapy. Mechanistically, ALDH1L2 interacts with thioredoxin (TXN) and regulates the downstream NF-κB signaling pathway. PX-12, the TXN inhibitor, overcomes radioresistance due to decreased ALDH1L2.

CONCLUSIONS:

Our results provide valuable insights into the potential role of ALDH1L2 in CRC radiotherapy. We propose that the simultaneous application of TXN inhibitors and radiotherapy would significantly ameliorate the clinical outcomes of patients with CRC having low ALDH1L2.

• Authors: Lu Yu, Qiqing Guo, Ziqian Luo, Yongjia Wang, Jiawen Weng, Yuchuan Chen, Weijie Liang, Yiyi Li, Yuqin Zhang, Keli Chen, Zhenhui Chen, Yi Ding, Yaowei Zhang
• Journal: British journal of cancer (Br J Cancer) Vol. 127 Issue 4 Pg. 637-648 (09 2022) ISSN: 1532-1827 [Electronic] England
• PMID: 35597868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• NF-kappa B
• Thioredoxins

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, genetics, radiotherapy)
• Gene Expression Regulation, Neoplastic
• Humans
• NF-kappa B (genetics, metabolism)
• Radiation Tolerance (genetics)
• Signal Transduction
• Thioredoxins (genetics, metabolism, therapeutic use)