AGTR1 potentiates the chemotherapeutic efficacy of cisplatin in esophageal carcinoma through elevation of intracellular Ca<sup>2+</sup> and induction of apoptosis

Liu,Kang; Bie,Jun; Zhang,Ruolan; Xiong,Rong; Peng,Lihong; Luo,Yi; Yang,Siyun; Feng,Gang; Song,Guiqin

doi:10.3892/ijo.2025.5738

AGTR1 potentiates the chemotherapeutic efficacy of cisplatin in esophageal carcinoma through elevation of intracellular Ca²⁺ and induction of apoptosis

Authors:
- Kang Liu
- Jun Bie
- Ruolan Zhang
- Rong Xiong
- Lihong Peng
- Yi Luo
- Siyun Yang
- Gang Feng
- Guiqin Song
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Affiliations: Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, Department of Oncology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
Published online on: March 10, 2025 https://doi.org/10.3892/ijo.2025.5738
Article Number: 32
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cisplatin is one of the principal chemotherapeutic agents used for esophageal cancer (EC) treatment; however, EC mortality remains high. It is therefore imperative to find new therapeutic targets and approaches to potentiate the chemotherapeutic efficacy of cisplatin. Angiotensin II receptor type 1 (AGTR1) is a potential therapeutic target in multiple cancer types. In the present study, RNA‑sequencing analysis of EC and normal esophageal tissues was performed and AGTR1 was identified as a differentially expressed gene that is markedly downregulated in recurrent and metastasized EC. AGTR1 upregulation in the esophageal squamous cell carcinoma cell lines, KYSE‑150 and EC109, promoted their chemosensitivity to cisplatin both in vitro and in vivo. Additionally, AGTR1 suppressed the metastasis‑relevant traits of EC cells, as evidenced by the reduced migration, invasion and wound healing of EC cells with higher AGTR1 expression levels. Moreover, AGTR1 overexpression in EC cells upregulated intracellular Ca²⁺ levels, reduced ATP levels and mitochondrial membrane potentials, which was accompanied by enhanced mitochondrial pathway apoptosis. Notably, either AGTR1 overexpression or treatments with the calcium channel blocker, fendiline, caused Ca²⁺ influx and promoted mitochondria‑dependent apoptosis in KYSE‑150 cells in vitro. These effects were augmented when both AGTR1 overexpression and fendiline stimulation were imposed in the absence or presence of cisplatin treatments. Furthermore, fendiline administration enhanced the chemosensitivity of cisplatin in an EC xenograft mouse model. Collectively, these findings offer an alternative treatment option and provide mechanistic insights into using fendiline to potentiate the chemotherapy efficacy of cisplatin in treating EC.

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