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08-09-2023 | Furosemide | Translational Research

Cancer Stem Cells of Esophageal Adenocarcinoma are Suppressed by Inhibitors of TRPV2 and SLC12A2

Authors: Atsushi Shiozaki, MD, PhD, Hiroyuki Inoue, MD, PhD, Hiroki Shimizu, MD, PhD, Toshiyuki Kosuga, MD, PhD, Kenichi Takemoto, MD, PhD, Michihiro Kudou, MD, PhD, Takuma Ohashi, MD, PhD, Tomohiro Arita, MD, PhD, Hirotaka Konishi, MD, PhD, Shuhei Komatsu, MD, PhD, Takeshi Kubota, MD, PhD, Hitoshi Fujiwara, MD, PhD, Eigo Otsuji, MD, PhD

Published in: Annals of Surgical Oncology | Issue 13/2023

Abstract

Background

The potential of membrane transporters activated in cancer stem cells (CSCs) as new therapeutic targets for cancer is attracting increasing interest. Therefore, the present study examined the expression profiles of ion transport-related molecules in the CSCs of esophageal adenocarcinoma (EAC).

Methods

Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from OE33 cells, a human Barrett’s EAC cell line, by fluorescence-activated cell sorting. CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were examined by a microarray analysis.

Results

Among OE33 cells, ALDH1A1 messenger RNA levels were higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels/transporters, such as transient receptor potential vanilloid 2 (TRPV2) and solute carrier family 12 member 2 (SLC12A2). The cytotoxicities of the TRPV2 inhibitor tranilast and the SLC12A2 inhibitor furosemide were higher at lower concentrations in CSCs than in non-CSCs, and both markedly reduced the number of tumorspheres. The cell population among OE33 cells that highly expressed ALDH1A1 also was significantly decreased by these inhibitors.

Conclusions

Based on the present results, TRPV2 and SLC12A2 are involved in the maintenance of CSCs, and their specific inhibitors, tranilast and furosemide, respectively, have potential as targeted therapeutic agents for EAC.

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Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49.PubMed

Watanabe M, Toh Y, Ishihara R, et al. Comprehensive registry of esophageal cancer in Japan, 2014. Esophagus. 2022;19(1):1–26.PubMed

Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am. 2002;11(2):235–56.PubMed

Morgan E, Soerjomataram I, Rumgay H, et al. The global landscape of esophageal squamous cell carcinoma and esophageal adenocarcinoma incidence and mortality in 2020 and projections to 2040: New estimates From GLOBOCAN 2020. Gastroenterology. 2022;163(3):649-58.e642.PubMed

Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014;371(26):2499–509.PubMed

Coleman HG, Xie SH, Lagergren J. The Epidemiology of Esophageal Adenocarcinoma. Gastroenterology. 2018;154(2):390–405.PubMed

Rumgay H, Arnold M, Laversanne M, et al. International trends in esophageal squamous cell carcinoma and adenocarcinoma incidence. Am J Gastroenterol. 2021;116(5):1072–6.PubMed

Koizumi S, Motoyama S, Iijima K. Is the incidence of esophageal adenocarcinoma increasing in Japan? Trends from the data of a hospital-based registration system in Akita Prefecture. Japan J Gastroenterol. 2018;53(7):827–33.PubMed

Shiozaki A, Ichikawa D, Otsuji E, Marunaka Y. Cellular physiological approach for treatment of gastric cancer. World J Gastroenterol. 2014;20(33):11560–6.PubMedPubMedCentral

10.

Shiozaki A, Marunaka Y, Otsuji E. Roles of ion and water channels in the cell death and survival of upper gastrointestinal tract cancers. Front Cell Dev Biol. 2021;9:616933.PubMedPubMedCentral

11.

Shiozaki A, Kudou M, Ichikawa D, et al. Esophageal cancer stem cells are suppressed by tranilast, a TRPV2 channel inhibitor. J Gastroenterol. 2018;53(2):197–207.PubMed

12.

Shiozaki A, Katsurahara K, Kudou M, et al. Amlodipine and verapamil, voltage-gated Ca(2+) channel inhibitors, suppressed the growth of gastric cancer stem cells. Ann Surg Oncol. 2021;28(9):5400–11.PubMed

13.

Shiozaki A, Konishi T, Kosuga T, et al. Roles of voltage-gated potassium channels in the maintenance of pancreatic cancer stem cells. Int J Oncol. 2021;59(4):1–18.

14.

Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8(10):755–68.PubMed

15.

Toh TB, Lim JJ, Chow EK. Epigenetics in cancer stem cells. Mol Cancer. 2017;16(1):29.PubMedPubMedCentral

16.

Darakhshan S, Pour AB. Tranilast: A review of its therapeutic applications. Pharmacol Res. 2015;91:15–28.PubMed

17.

Ajani JA, Wang X, Song S, et al. ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients. Mol Oncol. 2014;8(1):142–9.PubMed

18.

Honjo S, Ajani JA, Scott AW, et al. Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. Int J Oncol. 2014;45(2):567–74.PubMedPubMedCentral

19.

Song S, Xie M, Scott AW, et al. A novel YAP1 inhibitor targets CSC-enriched radiation-resistant cells and exerts strong antitumor activity in esophageal adenocarcinoma. Mol Cancer Ther. 2018;17(2):443–54.PubMed

20.

Wang Z, Da Silva TG, Jin K, et al. Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma. Cancer Res. 2014;74(21):6364–74.PubMedPubMedCentral

21.

Smit JK, Faber H, Niemantsverdriet M, et al. Prediction of response to radiotherapy in the treatment of esophageal cancer using stem cell markers. Radiother Oncol. 2013;107(3):434–41.PubMed

22.

Zhao Y, Bao Q, Schwarz B, et al. Stem cell-like side populations in esophageal cancer: a source of chemotherapy resistance and metastases. Stem Cells Dev. 2014;23(2):180–92.PubMed

23.

Perálvarez-Marín A, Doñate-Macian P, Gaudet R. What do we know about the transient receptor potential vanilloid 2 (TRPV2) ion channel? Febs J. 2013;280(21):5471–87.PubMedPubMedCentral

24.

Zhou K, Zhang SS, Yan Y, Zhao S. Overexpression of transient receptor potential vanilloid 2 is associated with poor prognosis in patients with esophageal squamous cell carcinoma. Med Oncol. 2014;31(7):17.PubMed

25.

Kudou M, Shiozaki A, Yamazato Y, et al. The expression and role of TRPV2 in esophageal squamous cell carcinoma. Sci Rep. 2019;9(1):16055.PubMedPubMedCentral

26.

Kato S, Shiozaki A, Kudou M, et al. TRPV2 promotes cell migration and invasion in gastric cancer via the transforming growth factor-β signaling pathway. Ann Surg Oncol. 2022;29(5):2944–56.PubMed

27.

Liu G, Xie C, Sun F, et al. Clinical significance of transient receptor potential vanilloid 2 expression in human hepatocellular carcinoma. Cancer Genet Cytogenet. 2010;197(1):54–9.PubMed

28.

Yamada T, Ueda T, Shibata Y, et al. TRPV2 activation induces apoptotic cell death in human T24 bladder cancer cells: a potential therapeutic target for bladder cancer. Urology. 2010;76(2):509.e501-507.

29.

Monet M, Lehen’kyi V, Gackiere F, et al. Role of cationic channel TRPV2 in promoting prostate cancer migration and progression to androgen resistance. Cancer Res. 2010;70(3):1225–35.PubMed

30.

Murahashi K, Yashiro M, Inoue T, et al. Tranilast and cisplatin as an experimental combination therapy for scirrhous gastric cancer. Int J Oncol. 1998;13(6):1235–40.PubMed

31.

Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19(1):68–74.PubMed

32.

Shiozaki A, Kudou M, Fujiwara H, et al. Clinical safety and efficacy of neoadjuvant combination chemotherapy of tranilast in advanced esophageal squamous cell carcinoma: Phase I/II study (TNAC). Medicine (Baltimore). 2020;99(50):e23633.PubMedPubMedCentral

33.

Stödberg T, Magnusson M, Lesko N, et al. SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia. Neurol Genet. 2020;6(4):e478.PubMedPubMedCentral

34.

Hebert SC, Mount DB, Gamba G. Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Pflugers Arch. 2004;447(5):580–93.PubMed

35.

Shiozaki A, Nako Y, Ichikawa D, et al. Role of the Na⁺/K⁺/2Cl⁻ cotransporter NKCC1 in cell cycle progression in human esophageal squamous cell carcinoma. World J Gastroenterol. 2014;20(22):6844–59.PubMedPubMedCentral

36.

Wang JF, Zhao K, Chen YY, et al. NKCC1 promotes proliferation, invasion and migration in human gastric cancer cells via activation of the MAPK-JNK/EMT signaling pathway. J Cancer. 2021;12(1):253–63.PubMedPubMedCentral

37.

Shiozaki A, Miyazaki H, Niisato N, et al. Furosemide, a blocker of Na+/K+/2Cl- cotransporter, diminishes proliferation of poorly differentiated human gastric cancer cells by affecting G0/G1 state. J Physiol Sci. 2006;56(6):401–6.PubMed

38.

Hiraoka K, Miyazaki H, Niisato N, et al. Chloride ion modulates cell proliferation of human androgen-independent prostatic cancer cell. Cell Physiol Biochem. 2010;25(4–5):379–88.PubMed

39.

Miyazaki H, Shiozaki A, Niisato N, et al. Chloride ions control the G1/S cell-cycle checkpoint by regulating the expression of p21 through a p53-independent pathway in human gastric cancer cells. Biochem Biophys Res Commun. 2008;366(2):506–12.PubMed

40.

Ohsawa R, Miyazaki H, Niisato N, et al. Intracellular chloride regulates cell proliferation through the activation of stress-activated protein kinases in MKN28 human gastric cancer cells. J Cell Physiol. 2010;223(3):764–70.PubMed

41.

Shiozaki A, Otsuji E, Marunaka Y. Intracellular chloride regulates the G(1)/S cell cycle progression in gastric cancer cells. World J Gastrointest Oncol. 2011;3(8):119–22.PubMedPubMedCentral

Title: Cancer Stem Cells of Esophageal Adenocarcinoma are Suppressed by Inhibitors of TRPV2 and SLC12A2
Authors: Atsushi Shiozaki, MD, PhD
Hiroyuki Inoue, MD, PhD
Hiroki Shimizu, MD, PhD
Toshiyuki Kosuga, MD, PhD
Kenichi Takemoto, MD, PhD
Michihiro Kudou, MD, PhD
Takuma Ohashi, MD, PhD
Tomohiro Arita, MD, PhD
Hirotaka Konishi, MD, PhD
Shuhei Komatsu, MD, PhD
Takeshi Kubota, MD, PhD
Hitoshi Fujiwara, MD, PhD
Eigo Otsuji, MD, PhD
Publication date: 08-09-2023
Publisher: Springer International Publishing
Keyword: Furosemide
Published in: Annals of Surgical Oncology / Issue 13/2023
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-023-14247-z

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Springer Medicine

Cancer Stem Cells of Esophageal Adenocarcinoma are Suppressed by Inhibitors of TRPV2 and SLC12A2

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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