Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2024; 30(4): 367-380
Published online Jan 28, 2024. doi: 10.3748/wjg.v30.i4.367
Amlodipine inhibits the proliferation and migration of esophageal carcinoma cells through the induction of endoplasmic reticulum stress
Yan-Min Chen, Wen-Qian Yang, Cheng-Wei Gu, Ying-Ying Fan, Yu-Zhen Liu, Bao-Sheng Zhao
Yan-Min Chen, Wen-Qian Yang, Cheng-Wei Gu, Yu-Zhen Liu, Bao-Sheng Zhao, Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Yan-Min Chen, Department of Oncology, The Affiliated Hospital, Henan Polytechnic University, Jiaozuo 454000, Henan Province, China
Wen-Qian Yang, Yu-Zhen Liu, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Ying-Ying Fan, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Author contributions: Chen YM, Liu YZ, and Zhao BS made substantial contributions to conception and design of the study; Chen YM and Yang WQ conducted the experiments, acquired and analyzed data; Chen YM, Yang WQ, Liu YZ, and Zhao BS interpreted the data; Gu CW and Fan YY were responsible for clinical sample collection; Chen YM and Liu YZ wrote the manuscript drift; Liu YZ and Zhao BS revised the manuscript; and all authors approved the final version of the manuscript.
Supported by the Key Medical Scientific and Technological Project of Henan Province, No. SBGJ202102188; Henan Provincial Medical Science and Technology Project, No. LHGJ20221012; and the Key Project of Science and Technology of Xinxiang, No. GG2020027.
Institutional review board statement: This study was reviewed and approved by the First Affiliated Hospital of Xinxiang Medical University Institutional Review Board (Approval No. EC-023-487).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the First Affiliated Hospital of Xinxiang Medical University Institutional Review Board (Approval No. EC-023-488).
Conflict-of-interest statement: The authors declare that no conflict of interest exists in this study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bao-Sheng Zhao, BMed, Chief Physician, Professor, Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui 453100, Henan Province, China. drbszhao@xxmu.edu.cn
Received: December 12, 2023
Peer-review started: December 12, 2023
First decision: December 19, 2023
Revised: December 21, 2023
Accepted: January 3, 2024
Article in press: January 3, 2024
Published online: January 28, 2024
Processing time: 45 Days and 4.1 Hours
Abstract
BACKGROUND

L-type calcium channels are the only protein channels sensitive to calcium channel blockers, and are expressed in various cancer types. The Cancer Genome Atlas database shows that the mRNA levels of multiple L-type calcium channel subunits in esophageal squamous cell carcinoma tumor tissue are significantly higher than those in normal esophageal epithelial tissue. Therefore, we hypothesized that amlodipine, a long-acting dihydropyridine L-type calcium channel blocker, may inhibit the occurrence and development of esophageal cancer (EC).

AIM

To investigate the inhibitory effects of amlodipine on EC through endoplasmic reticulum (ER) stress.

METHODS

Cav1.3 protein expression levels in 50 pairs of EC tissues and corresponding paracancerous tissues were examined. Subsequently, the inhibitory effects of amlodipine on proliferation and migration of EC cells in vitro were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and Transwell assays. In vivo experiments were performed using murine xenograft model. To elucidate the underlying mechanisms, in vitro cell studies were performed to confirm that ER stress plays a role in inhibition proliferation and migration of EC cells treated with amlodipine.

RESULTS

The expression level of Cav1.3 in esophageal carcinoma was 1.6 times higher than that in paracancerous tissues. Amlodipine treatment decreased the viability of esophageal carcinoma cells in a dose- and time-dependent manner. In vivo animal experiments also clearly indicated that amlodipine inhibited the growth of EC tumors in mice. Additionally, amlodipine reduces the migration of tumor cells by inhibiting epithelial-mesenchymal transition (EMT). Mechanistic studies have demonstrated that amlodipine induces ER stress-mediated apoptosis and suppresses EMT. Moreover, amlodipine-induced autophagy was characterized by an increase in autophagy lysosomes and the accumulation of light chain 3B protein. The combination of amlodipine with the ER stress inhibitor 4-phenylbutyric acid further confirmed the role of the ER stress response in amlodipine-induced apoptosis, EMT, and autophagy. Furthermore, blocking autophagy increases the ratio of apoptosis and migration.

CONCLUSION

Collectively, we demonstrate for the first time that amlodipine promotes apoptosis, induces autophagy, and inhibits migration through ER stress, thereby exerting anti-tumor effects in EC.

Keywords: L-type calcium channel; Amlodipine; Esophageal cancer; Autophagy; Endoplasmic reticulum stress

Core Tip: L-type calcium channel blockers have been shown to inhibit the growth of various tumors. We observed a higher expression of the L-type calcium channel Cav1.3 in esophageal cancer (EC) tissue than in paracancerous tissues. Subsequently, we confirmed that amlodipine inhibited the development of EC both in vivo and in vitro. Finally, we established that this inhibitory effect is related to the activation of endoplasmic reticulum stress.