Telmisartan affects proliferation, migration and apoptosis of non-small cell lung cancer cell A549 through the Wnt/β-catenin signaling pathway_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANG Lingjie ¹ , ZHAO Donghua ¹ , HUANG Zhangfeng ¹ , LI Mengjun ¹ , GUO Pengfei ¹ ,  WANG Yongjie ²

1. Qingdao Medical College of Qingdao University, Qingdao, 266071, Shandong, P.R.China;
2. Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266071, Shandong, P.R.China;

Corresponding author：

WANG Yongjie, Email: wangyongjie317@163.com

Keywords：

Telmisartan; lung cancer; apoptosis; Wnt/β-catenin signaling pathway

DOI：

10.7507/1007-4848.202010077

Video：

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Objective To investigate the effects of telmisartan on the proliferation, migration and apoptosis of non-small cell lung cancer A549 and the mechanism of regulating Wnt signaling pathway.Methods Non-small cell lung cancer cell line A549 was cultured in vitro. Cell counting kit-8 (CCK-8) assay was used to detect the effect of telmisartan at different concentrations on the proliferative activity of A549 cells. The survival fraction of A549 treated with different concentrations of telmisartan was determined by colony-formation assay. The effect of telmisartan at different concentrations on the migration ability of A549 cells was examined in the wounding healing assay. Hoechst staining was used to detect the effects of telmisartan at different concentrations on the apoptosis of A549. Western bloting was used to detect the expressions of β-actin, proliferating cell nuclear antigen (PCNA), Bax, Bcl-2, Wnt-3a, Beta-catenin (β-catenin), serine protein kinase 3β (p-GSK-3β), glycogen synthase kinase-3β (GSK-3β) and c-myc.Results Different concentrations of telmisartan treatment inhibited the proliferation activity, colony-formation rate and migration of A549 cells, and reduced the expression of PCNA in a concentration-dependent manner. Telmisartan treatment promoted the apoptosis of A549 cells, significantly increased the expression of pro-apoptotic protein Bax and decreased the expression of anti-apoptotic protein Bcl-2. The expression levels of Wnt-3a, β-catenin, p-GSK-3β, and c-myc in A549 cells increased after treatment with telmisartan, while the expression levels of GSK-3β decreased.Conclusion Telmisartan may play a role in the proliferation, migration and apoptosis of non-small cell lung cancer A549 cells, and inhibiting the Wnt/β-catenin signaling pathway may be one of the mechanisms.

Citation： WANG Lingjie, ZHAO Donghua, HUANG Zhangfeng, LI Mengjun, GUO Pengfei, WANG Yongjie. Telmisartan affects proliferation, migration and apoptosis of non-small cell lung cancer cell A549 through the Wnt/β-catenin signaling pathway. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2022, 29(1): 100-105. doi: 10.7507/1007-4848.202010077 Copy

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2.	Hoy H, Lynch T, Beck M. Surgical treatment of lung cancer. Crit Care Nurs Clin North Am, 2019, 31(3): 303-313.
3.	Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: Current therapies and new targeted treatments. Lancet, 2017, 389(10066): 299-311.
4.	Pu Z, Zhu M, Kong F. Telmisartan prevents proliferation and promotes apoptosis of human ovarian cancer cells through upregulating PPARγ and downregulating MMP-9 expression. Mol Med Rep, 2016, 13(1): 555-559.
5.	Fujita N, Fujita K, Iwama H, et al. Antihypertensive drug telmisartan suppresses the proliferation of gastric cancer cells in vitro and in vivo. Oncol Rep, 2020, 44(1): 339-348.
6.	Wu TT, Niu HS, Chen LJ, et al. Increase of human prostate cancer cell (DU145) apoptosis by telmisartan through PPAR-delta pathway. Eur J Pharmacol, 2016, 775: 35-42.
7.	Green R, Howell M, Khalil R, et al. Actinomycin D and telmisartan combination targets lung cancer stem cells through the Wnt/beta catenin pathway. Sci Rep, 2019, 9: 18177.
8.	Zhang S, Wang Y. Telmisartan inhibits NSCLC A549 cell proliferation and migration by regulating the PI3K/AKT signaling pathway. Oncol Lett, 2018, 15(4): 5859-5864.
9.	Song Z, Wang H, Zhang S, et al. Negative regulators of Wnt signaling in non-small cell lung cancer: Theoretical basis and therapeutic potency. Biomed Pharmacother, 2019, 118: 109336.
10.	魏燕, 金剑虹, 侯鹏超. 利拉鲁肽联合替米沙坦洽疗糖尿病肾病患者的临床研究. 中国临床药理学杂志, 2020, 36(2): 106-109.
11.	Tascilar K, Azoulay L, Dell'Aniello S, et al. The use of telmisartan and the incidence of cancer. Am J Hypertens, 2016, 29(12): 1358-1365.
12.	Sipahi I, Debanne SM, Rowland DY, et al. Angiotensin-receptor blockade and risk of cancer: Meta-analysis of randomised controlled trials. Lancet Oncol, 2010, 11(7): 627-636.
13.	Grahovac J, Srdić-Rajić T, Francisco Santibañez J, et al. Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics. Cancer Biol Med, 2019, 16(2): 247-263.
14.	Matsui T, Chiyo T, Kobara H, et al. Telmisartan inhibits cell proliferation and tumor growth of esophageal squamous cell carcinoma by inducing s-phase arrest in vitro and in vivo. Int J Mol Sci, 2019, 20(13): 3197.
15.	Sukumaran S, Patel HJ, Patel BM. Evaluation of role of telmisartan in combination with 5-fluorouracil in gastric cancer cachexia. Life Sci, 2016, 154: 15-23.
16.	ÖztÜrk N, Kara A, Vural İ. Formulation and in vitro evaluation of telmisartan nanoparticles prepared by emulsion-solvent evaporation technique. Turk J Pharm Sci, 2020, 17(5): 492-499.
17.	Kobara H, Fujihara S, Iwama H, et al. Antihypertensive drug telmisartan inhibits cell proliferation of gastrointestinal stromal tumor cells in vitro. Mol Med Rep, 2020, 22(2): 1063-1071.
18.	Wadsworth BJ, Cederberg RA, Lee CM, et al. Angiotensin Ⅱ type 1 receptor blocker telmisartan inhibits the development of transient hypoxia and improves tumour response to radiation. Cancer Lett, 2020, 493: 31-40.
19.	Rasheduzzaman M, Moon JH, Lee JH, et al. Telmisartan generates ROS-dependent upregulation of death receptor 5 to sensitize TRAIL in lung cancer via inhibition of autophagy flux. Int J Biochem Cell Biol, 2018, 102: 20-30.
20.	To KKW, Wu WKK, Loong HHF. PPARgamma agonists sensitize PTEN-deficient resistant lung cancer cells to EGFR tyrosine kinase inhibitors by inducing autophagy. Eur J Pharmacol, 2018, 823: 19-26.
21.	Patel K, Doddapaneni R, Sekar V, et al. Combination approach of YSA peptide anchored docetaxel stealth liposomes with oral antifibrotic agent for the treatment of lung cancer. Mol Pharm, 2016, 13(6): 2049-2058.
22.	Godugu C, Patel AR, Doddapaneni R, et al. Inhalation delivery of Telmisartan enhances intratumoral distribution of nanoparticles in lung cancer models. J Control Release, 2013, 172(1): 86-95.
23.	Martínez VR, Aguirre MV, Todaro JS, et al. Improvement of the anticancer activities of telmisartan by Zn(Ⅱ) complexation and mechanisms of action. Biol Trace Elem Res, 2020, 197(2): 454-463.
24.	Matsui WH. Cancer stem cell signaling pathways. Medicine (Baltimore), 2016, 95(1 Suppl 1): S8-S19.
25.	Hosoda A, Matsumoto Y, Toriyama Y, et al. Telmisartan exacerbates cisplatin-induced nephrotoxicity in a mouse model. Biol Pharm Bull, 2020, 43(9): 1331-1337.

1. Mao Y, Yang D, He J, et al. Epidemiology of lung cancer. Surg Oncol Clin N Am, 2016, 25(3): 439-445.
2. Hoy H, Lynch T, Beck M. Surgical treatment of lung cancer. Crit Care Nurs Clin North Am, 2019, 31(3): 303-313.
3. Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: Current therapies and new targeted treatments. Lancet, 2017, 389(10066): 299-311.
4. Pu Z, Zhu M, Kong F. Telmisartan prevents proliferation and promotes apoptosis of human ovarian cancer cells through upregulating PPARγ and downregulating MMP-9 expression. Mol Med Rep, 2016, 13(1): 555-559.
5. Fujita N, Fujita K, Iwama H, et al. Antihypertensive drug telmisartan suppresses the proliferation of gastric cancer cells in vitro and in vivo. Oncol Rep, 2020, 44(1): 339-348.
6. Wu TT, Niu HS, Chen LJ, et al. Increase of human prostate cancer cell (DU145) apoptosis by telmisartan through PPAR-delta pathway. Eur J Pharmacol, 2016, 775: 35-42.
7. Green R, Howell M, Khalil R, et al. Actinomycin D and telmisartan combination targets lung cancer stem cells through the Wnt/beta catenin pathway. Sci Rep, 2019, 9: 18177.
8. Zhang S, Wang Y. Telmisartan inhibits NSCLC A549 cell proliferation and migration by regulating the PI3K/AKT signaling pathway. Oncol Lett, 2018, 15(4): 5859-5864.
9. Song Z, Wang H, Zhang S, et al. Negative regulators of Wnt signaling in non-small cell lung cancer: Theoretical basis and therapeutic potency. Biomed Pharmacother, 2019, 118: 109336.
10. 魏燕, 金剑虹, 侯鹏超. 利拉鲁肽联合替米沙坦洽疗糖尿病肾病患者的临床研究. 中国临床药理学杂志, 2020, 36(2): 106-109.
11. Tascilar K, Azoulay L, Dell'Aniello S, et al. The use of telmisartan and the incidence of cancer. Am J Hypertens, 2016, 29(12): 1358-1365.
12. Sipahi I, Debanne SM, Rowland DY, et al. Angiotensin-receptor blockade and risk of cancer: Meta-analysis of randomised controlled trials. Lancet Oncol, 2010, 11(7): 627-636.
13. Grahovac J, Srdić-Rajić T, Francisco Santibañez J, et al. Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics. Cancer Biol Med, 2019, 16(2): 247-263.
14. Matsui T, Chiyo T, Kobara H, et al. Telmisartan inhibits cell proliferation and tumor growth of esophageal squamous cell carcinoma by inducing s-phase arrest in vitro and in vivo. Int J Mol Sci, 2019, 20(13): 3197.
15. Sukumaran S, Patel HJ, Patel BM. Evaluation of role of telmisartan in combination with 5-fluorouracil in gastric cancer cachexia. Life Sci, 2016, 154: 15-23.
16. ÖztÜrk N, Kara A, Vural İ. Formulation and in vitro evaluation of telmisartan nanoparticles prepared by emulsion-solvent evaporation technique. Turk J Pharm Sci, 2020, 17(5): 492-499.
17. Kobara H, Fujihara S, Iwama H, et al. Antihypertensive drug telmisartan inhibits cell proliferation of gastrointestinal stromal tumor cells in vitro. Mol Med Rep, 2020, 22(2): 1063-1071.
18. Wadsworth BJ, Cederberg RA, Lee CM, et al. Angiotensin Ⅱ type 1 receptor blocker telmisartan inhibits the development of transient hypoxia and improves tumour response to radiation. Cancer Lett, 2020, 493: 31-40.
19. Rasheduzzaman M, Moon JH, Lee JH, et al. Telmisartan generates ROS-dependent upregulation of death receptor 5 to sensitize TRAIL in lung cancer via inhibition of autophagy flux. Int J Biochem Cell Biol, 2018, 102: 20-30.
20. To KKW, Wu WKK, Loong HHF. PPARgamma agonists sensitize PTEN-deficient resistant lung cancer cells to EGFR tyrosine kinase inhibitors by inducing autophagy. Eur J Pharmacol, 2018, 823: 19-26.
21. Patel K, Doddapaneni R, Sekar V, et al. Combination approach of YSA peptide anchored docetaxel stealth liposomes with oral antifibrotic agent for the treatment of lung cancer. Mol Pharm, 2016, 13(6): 2049-2058.
22. Godugu C, Patel AR, Doddapaneni R, et al. Inhalation delivery of Telmisartan enhances intratumoral distribution of nanoparticles in lung cancer models. J Control Release, 2013, 172(1): 86-95.
23. Martínez VR, Aguirre MV, Todaro JS, et al. Improvement of the anticancer activities of telmisartan by Zn(Ⅱ) complexation and mechanisms of action. Biol Trace Elem Res, 2020, 197(2): 454-463.
24. Matsui WH. Cancer stem cell signaling pathways. Medicine (Baltimore), 2016, 95(1 Suppl 1): S8-S19.
25. Hosoda A, Matsumoto Y, Toriyama Y, et al. Telmisartan exacerbates cisplatin-induced nephrotoxicity in a mouse model. Biol Pharm Bull, 2020, 43(9): 1331-1337.

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Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Telmisartan affects proliferation, migration and apoptosis of non-small cell lung cancer cell A549 through the Wnt/β-catenin signaling pathway

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