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

April-2025 Volume 66 Issue 4

Full Size Image

Cover Legend PDF

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

April-2025 Volume 66 Issue 4

Full Size Image

Cover Legend PDF

Article Open Access

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
View Affiliations / Copyright

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

Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 32
|
Published online on: March 10, 2025

https://doi.org/10.3892/ijo.2025.5738
Expand metrics +

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.

View Figures

View References

1	Huang FL and Yu SJ: Esophageal cancer: Risk factors, genetic association, and treatment. Asian J Surg. 41:210–215. 2018. View Article : Google Scholar
2	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
3	Arnal MJ, Arenas AF and Arbeloa AL: Esophageal cancer: Risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol. 21:7933–7943. 2015. View Article : Google Scholar
4	Yang YM, Hong P, Xu WW, He QY and Li B: Advances in targeted therapy for esophageal cancer. Signal Transduct Target Ther. 5:2292020. View Article : Google Scholar : PubMed/NCBI
5	Borggreve AS, Kingma BF, Domrachev SA, Koshkin MA, Ruurda JP, van Hillegersberg R, Takeda FR and Goense L: Surgical treatment of esophageal cancer in the era of multimodality management. Ann N Y Acad Sci. 1434:192–209. 2018. View Article : Google Scholar : PubMed/NCBI
6	Ku GY: Systemic therapy for esophageal cancer: Chemotherapy. Chin Clin Oncol. 6:492017. View Article : Google Scholar : PubMed/NCBI
7	Luan S, Zeng X, Zhang C, Qiu J, Yang Y, Mao C, Xiao X, Zhou J, Zhang Y and Yuan Y: Advances in drug resistance of esophageal cancer: From the perspective of tumor microenvironment. Front Cell Dev Biol. 9:6648162021. View Article : Google Scholar : PubMed/NCBI
8	Ilson DH, Forastiere A, Arquette M, Costa F, Heelan R, Huang Y and Kelsen DP: A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer J. 6:316–323. 2000.PubMed/NCBI
9	Li Z, Zhang P, Ma Q, Wang D and Zhou T: Cisplatin-based chemoradiotherapy with 5-fluorouracil or pemetrexed in patients with locally advanced, unresectable esophageal squamous cell carcinoma: A retrospective analysis. Mol Clin Oncol. 6:743–747. 2017. View Article : Google Scholar : PubMed/NCBI
10	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI
11	Cui C, Merritt R, Fu L and Pan Z: Targeting calcium signaling in cancer therapy. Acta Pharm Sin B. 7:3–17. 2017. View Article : Google Scholar : PubMed/NCBI
12	Dubois C, Abeele FV and Prevarskaya N: Targeting apoptosis by the remodelling of calcium-transporting proteins in cancerogenesis. FEBS J. 280:5500–5510. 2013. View Article : Google Scholar : PubMed/NCBI
13	Al-Bahlani S, Fraser M, Wong AY, Sayan BS, Bergeron R, Melino G and Tsang BK: P73 regulates cisplatin-induced apoptosis in ovarian cancer cells via a calcium/calpain-dependent mechanism. Oncogene. 30:4219–4230. 2011. View Article : Google Scholar : PubMed/NCBI
14	Gualdani R, de Clippele M, Ratbi I, Gailly P and Tajeddine N: Store-Operated calcium entry contributes to cisplatin-induced cell death in non-small cell lung carcinoma. Cancers (Basel). 11:4302019. View Article : Google Scholar : PubMed/NCBI
15	Shen L, Wen N, Xia M, Zhang YU, Liu W, Xu YE and Sun L: Calcium efflux from the endoplasmic reticulum regulates cisplatin-induced apoptosis in human cervical cancer HeLa cells. Oncol Lett. 11:2411–2419. 2016. View Article : Google Scholar : PubMed/NCBI
16	Singh KD and Karnik SS: Angiotensin receptors: Structure, function, signaling and clinical applications. J Cell Signal (Los Angel). 1:1112016.PubMed/NCBI
17	Barreras A and Gurk-Turner C: Angiotensin II receptor blockers. Proc (Bayl Univ Med Cent). 16:123–126. 2003.
18	Rhodes DR, Ateeq B, Cao Q, Tomlins SA, Mehra R, Laxman B, Kalyana-Sundaram S, Lonigro RJ, Helgeson BE, Bhojani MS, et al: AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist. Proc Natl Acad Sci USA. 106:10284–10289. 2009. View Article : Google Scholar : PubMed/NCBI
19	Ma Y, Xia Z, Ye C, Lu C, Zhou S, Pan J, Liu C, Zhang J, Liu T, Hu T, et al: AGTR1 promotes lymph node metastasis in breast cancer by upregulating CXCR4/SDF-1alpha and inducing cell migration and invasion. Aging (Albany NY). 11:3969–3992. 2019. View Article : Google Scholar : PubMed/NCBI
20	Ateeq B, Tomlins SA and Chinnaiyan AM: AGTR1 as a therapeutic target in ER-positive and ERBB2-negative breast cancer cases. Cell Cycle. 8:3794–3795. 2009. View Article : Google Scholar : PubMed/NCBI
21	Suganuma T, Ino K, Shibata K, Kajiyama H, Nagasaka T, Mizutani S and Kikkawa F: Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis, and peritoneal dissemination. Clin Cancer Res. 11:2686–2694. 2005. View Article : Google Scholar : PubMed/NCBI
22	Pu Y, Zhao F, Li Y, Cui M, Wang H, Meng X and Cai S: The miR-34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene. BMC Cancer. 17:452017. View Article : Google Scholar : PubMed/NCBI
23	Kooptiwut S, Hanchang W, Semprasert N, Junking M, Limjindaporn T and Yenchitsomanus PT: Testosterone reduces AGTR1 expression to prevent β-cell and islet apoptosis from glucotoxicity. J Endocrinol. 224:215–224. 2015. View Article : Google Scholar
24	Kooptiwut S, Wanchai K, Semprasert N, Srisawat C and Yenchitsomanus PT: Estrogen attenuates AGTR1 expression to reduce pancreatic β-cell death from high glucose. Sci Rep. 7:166392017. View Article : Google Scholar
25	Wang W, Sun L, Xiao W and Yang H: Essential role of angiotensin receptors in the modulation of intestinal epithelial cell apoptosis. J Pediatr Gastroenterol Nutr. 57:562–569. 2013. View Article : Google Scholar : PubMed/NCBI
26	Yang Y, Zhou Y, Cao Z, Tong XZ, Xie HQ, Luo T, Hua XP and Wang HQ: miR-155 functions downstream of angiotensin II receptor subtype 1 and calcineurin to regulate cardiac hypertrophy. Exp Ther Med. 12:1556–1562. 2016. View Article : Google Scholar : PubMed/NCBI
27	Berry MF: Esophageal cancer: Staging system and guidelines for staging and treatment. J Thorac Dis. 6(Suppl 3): S289–S297. 2014.PubMed/NCBI
28	Boonstra JJ, van der Velden AW, Beerens EC, van Marion R, Morita-Fujimura Y, Matsui Y, Nishihira T, Tselepis C, Hainaut P, Lowe AW, et al: Mistaken identity of widely used esophageal adenocarcinoma cell line TE-7. Cancer Res. 67:7996–8001. 2007. View Article : Google Scholar : PubMed/NCBI
29	Capes-Davis A, Theodosopoulos G, Atkin I, Drexler HG, Kohara A, MacLeod RA, Masters JR, Nakamura Y, Reid YA, Reddel RR and Freshney RI: Check your cultures! A list of cross-contaminated or misidentified cell lines. Int J Cancer. 127:1–8. 2010. View Article : Google Scholar : PubMed/NCBI
30	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
31	Liu CQ, Ma YL, Qin Q, Wang PH, Luo Y, Xu PF and Cui Y: Epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040. Thorac Cancer. 14:3–11. 2023. View Article : Google Scholar :
32	Zhu H, Wang Z, Deng B, Mo M, Wang H, Chen K, Wu H, Ye T, Wang B, Ai D, et al: Epidemiological landscape of esophageal cancer in Asia: Results from GLOBOCAN 2020. Thorac Cancer. 14:992–1003. 2023. View Article : Google Scholar : PubMed/NCBI
33	Uhlenhopp DJ, Then EO, Sunkara T and Gaduputi V: Epidemiology of esophageal cancer: Update in global trends, etiology and risk factors. Clin J Gastroenterol. 13:1010–1021. 2020. View Article : Google Scholar : PubMed/NCBI
34	Brown A, Kumar S and Tchounwou PB: Cisplatin-Based chemotherapy of human cancers. J Cancer Sci Ther. 11:972019.PubMed/NCBI
35	Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, et al: Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 4:25162013. View Article : Google Scholar : PubMed/NCBI
36	Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y and Jain RK: Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci USA. 108:2909–2914. 2011. View Article : Google Scholar : PubMed/NCBI
37	Zhang Q, Yu S, Lam MMT, Poon TCW, Sun L, Jiao Y, Wong AST and Lee LT: Angiotensin II promotes ovarian cancer spheroid formation and metastasis by upregulation of lipid desaturation and suppression of endoplasmic reticulum stress. J Exp Clin Cancer Res. 38:1162019. View Article : Google Scholar : PubMed/NCBI
38	Li SH, Lu HI, Chang AY, Huang WT, Lin WC, Lee CC, Tien WY, Lan YC, Tsai HT and Chen CH: Angiotensin II type I receptor (AT1R) is an independent prognosticator of esophageal squamous cell carcinoma and promotes cells proliferation via mTOR activation. Oncotarget. 7:67150–67165. 2016. View Article : Google Scholar : PubMed/NCBI
39	Fujihara S, Morishita A, Ogawa K, Tadokoro T, Chiyo T, Kato K, Kobara H, Mori H, Iwama H and Masaki T: The angiotensin II type 1 receptor antagonist telmisartan inhibits cell proliferation and tumor growth of esophageal adenocarcinoma via the AMPKalpha/mTOR pathway in vitro and in vivo. Oncotarget. 8:8536–8549. 2017. View Article : Google Scholar : PubMed/NCBI
40	Guo DF, Sun YL, Hamet P and Inagami T: The angiotensin II type 1 receptor and receptor-associated proteins. Cell Res. 11:165–180. 2001. View Article : Google Scholar : PubMed/NCBI
41	Rizzuto R, Pinton P, Ferrari D, Chami M, Szabadkai G, Magalhães PJ, Di Virgilio F and Pozzan T: Calcium and apoptosis: Facts and hypotheses. Oncogene. 22:8619–8627. 2003. View Article : Google Scholar : PubMed/NCBI
42	Giorgi C, Baldassari F, Bononi A, Bonora M, De Marchi E, Marchi S, Missiroli S, Patergnani S, Rimessi A, Suski JM, et al: Mitochondrial Ca(2+) and apoptosis. Cell Calcium. 52:36–43. 2012. View Article : Google Scholar : PubMed/NCBI
43	Schulz J, Lubnau E, Grossmann M and Rück W: Double-blind, randomized study of the anti-anginal and anti-ischaemic efficacy of fendiline and diltiazem in patients with coronary heart disease. Curr Med Res Opin. 12:521–539. 1991. View Article : Google Scholar : PubMed/NCBI
44	Bayer R and Mannhold R: Fendiline: A review of its basic pharmacological and clinical properties. Pharmatherapeutica. 5:103–136. 1987.PubMed/NCBI
45	Fassbender V, Wegener JW, Shainberg A and Nawrath H: Inhibition by fendiline of the transient outward current in rat ventricular cardiomyocytes. J Cardiovasc Pharmacol. 33:905–911. 1999. View Article : Google Scholar : PubMed/NCBI
46	Nawrath H, Klein G, Rupp J, Wegener JW and Shainberg A: Open state block by fendiline of L-type Ca++ channels in ventricular myocytes from rat heart. J Pharmacol Exp Ther. 285:546–552. 1998. View Article : Google Scholar : PubMed/NCBI
47	Tripathi O, Schreibmayer W and Tritthart HA: Fendiline inhibits L-type calcium channels in guinea-pig ventricular myocytes: A whole-cell patch-clamp study. Br J Pharmacol. 108:865–869. 1993. View Article : Google Scholar : PubMed/NCBI
48	Lin MC and Jan CR: The anti-anginal drug fendiline elevates cytosolic Ca(2+) in rabbit corneal epithelial cells. Life Sci. 71:1071–1079. 2002. View Article : Google Scholar : PubMed/NCBI
49	Jan CR, Lee KC, Chou KJ, Cheng JS, Wang JL, Lo YK, Chang HT, Tang KY, Yu CC and Huang JK: Fendiline, an anti-anginal drug, increases intracellular Ca2+ in PC3 human prostate cancer cells. Cancer Chemother Pharmacol. 48:37–41. 2001. View Article : Google Scholar : PubMed/NCBI
50	Huang C, Huang C, Cheng J, Liu S, Chen I, Tsai J, Chou C, Tseng P and Jan C: Fendiline-evoked [Ca2+]i rises and non-Ca2+-triggered cell death in human oral cancer cells. Hum Exp Toxicol. 28:41–48. 2009. View Article : Google Scholar : PubMed/NCBI
51	Woods N, Trevino J, Coppola D, Chellappan S, Yang S and Padmanabhan J: Fendiline inhibits proliferation and invasion of pancreatic cancer cells by interfering with ADAM10 activation and β-catenin signaling. Oncotarget. 6:35931–35948. 2015. View Article : Google Scholar : PubMed/NCBI
52	Cheng JS, Wang JL, Lo YK, Chou KJ, Lee KC, Liu CP, Chang HT and Jan CR: Effects of the antianginal drug fendiline on Ca2+ movement in hepatoma cells. Hum Exp Toxicol. 20:359–364. 2001. View Article : Google Scholar : PubMed/NCBI
53	Wang J, Cheng J, Chan R, Tseng L, Chou K, Tang K, Lee KC, Lo Y, Wang J and Jan C: The anti-anginal drug fendiline increases intracellular Ca(2+) levels in MG63 human osteosarcoma cells. Toxicol Lett. 119:227–233. 2001. View Article : Google Scholar : PubMed/NCBI
54	Alhothali M, Mathew M, Iyer G, Lawrence HR, Yang S, Chellappan S and Padmanabhan J: Fendiline enhances the cytotoxic effects of therapeutic agents on PDAC cells by inhibiting tumor-promoting signaling events: A potential strategy to combat PDAC. Int J Mol Sci. 20:24232019. View Article : Google Scholar : PubMed/NCBI
55	Brizzolara A, Garbati P, Vella S, Calderoni M, Quattrone A, Tonini GP, Capasso M, Longo L, Barbieri R, Florio T and Pagano A: Co-Administration of fendiline hydrochloride enhances chemotherapeutic efficacy of cisplatin in neuroblastoma treatment. Molecules. 25:52342020. View Article : Google Scholar : PubMed/NCBI
56	van der Hoeven D, Cho KJ, Ma X, Chigurupati S, Parton RG and Hancock JF: Fendiline inhibits K-Ras plasma membrane localization and blocks K-Ras signal transmission. Mol Cell Biol. 33:237–251. 2013. View Article : Google Scholar :

Journals