Paeoniflorin inhibits the growth of bladder carcinoma via deactivation of STAT3

Open access

Abstract

Bladder cancer (BCa) is one of the most common urinary cancers. The present study aims to investigate whether Paeoniflorin (Pae) can exert inhibitory effects on BCa. The results showed that Pae inhibited proliferation of human BCa cell lines in a concentration- and time-dependent manner. Pae and cisplatin (Cis) synergistically inhibited the growth of tumours in RT4-bearing mice. Pae treatment neutralized the body loss induced by Cis. Moreover, Pae induced apoptosis in RT4 cells and increased the activities of caspase3, caspase8 and caspase9. Western blotting and immunohistochemical analysis revealed that the phosphorylated signal transducer and activator of transcription-3 (p-STAT3) level were decreased in Pae-treated RT4 cells and Pae-treated tumour-bearing mice. Furthermore, STAT3 transcriptional target B-cell lymphoma-2 was decreased in Pae-treated RT4 cells. Interestingly, Pae prevented translocation of STAT3 to the nucleus in RT4 cells. Collectively, Pae inhibits the growth of BCa, at least in part, via a STAT3 pathway.

1. M. Peng, Y. Huang, T. Tao, C. Y. Peng, Q. Su, W. Xu, K. O. Darko, X. Tao and X. Yang, Metformin and gefitinib cooperate to inhibit bladder cancer growth via both AMPK and EGFR pathways joining at Akt and Erk, Sci. Rep. 6 (2016) 28611; https://doi.org/10.1038/srep28611

2. R. Arantes-Rodrigues, R. Pinto-Leite, L. Fidalgo-Gonçalves, C. Palmeira, L. Santos, A. Colaço and P. Oliveira, Synergistic effect between cisplatin and sunitinib malate on human urinary bladder-cancer cell lines, Biomed. Res. Int. (2013) 791406; https://doi.org/10.1155/2013/791406

3. E. W. Gerharz, A. Månsson and W. Månsson, Quality of life in patients with bladder cancer, Urol. Oncol. 23 (2005) 201–207; https://doi.org/10.1016/j.urolonc.2005.03.005

4. E. J. Hillmer, H. Zhang, H. S. Li and S. S. Watowich, STAT3 signaling in immunity, Cytokine Growth Factor Rev. 31 (2016) 1–15; https://doi.org/10.1016/j.cytogfr.2016.05.001

5. S. Bhattacharya, R. M. Ray and L. R. Johnson, STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells, Biochem. J. 392 (2005) 335–344; https://doi.org/10.1042/BJ20050465

6. J. Bromberg and J. E. Jr. Darnell, The role of STATs in transcriptional control and their impact on cellular function, Oncogene 19 (2000) 2468–2473; https://doi.org/10.1038/sj.onc.1203476

7. M. Degoricija, M. Situm, J. Korać, A. Miljković, K. Matić, M. Paradžik, I. Marinović Terzić, A. Jerončić, S. Tomić and J. Terzić, High NF-κB and STAT3 activity in human urothelial carcinoma: a pilot study, World. J. Urol. 32 (2014) 1469–1475; https://doi.org/10.1007/s00345-014-1237-1

8. B. Zhang, Z. Lu, Y. Hou, J. Hu and C. Wang, The effects of STAT3 and Survivin silencing on the growth of human bladder carcinoma cells, Tumour Biol. 35 (2014) 5401–5407; https://doi.org/10.1007/s13277-014-1704-8

9. H. H. Yeh, R. Giri, T. Y. Chang, C. Y. Chou, W. C. Su and H. S. Liu, Ha-ras oncogene-induced Stat3 phosphorylation enhances oncogenicity of the cell, DNA. Cell. Biol. 28 (2009) 131–139; https://doi.org/10.1089/dna.2008.0762

10. R. J. Chen, Y. S. Ho, H. R. Guo and Y. J. Wang, Long-term nicotine exposure-induced chemoresistance is mediated by activation of Stat3 and downregulation of ERK1/2 via nAChR and beta- adrenoceptors in human bladder cancer cells, Toxicol. Sci. 115 (2010) 118–130; https://doi.org/10.1093/toxsci/kfq028

11. S. Parker, B. May, C. Zhang, A. L. Zhang, C. Lu and C. C. Xue, A pharmacological review of bioactive constituents of Paeonia lactiflora Pallas and Paeonia veitchii Lynch, Phytother. Res. 30 (2016) 1445–1473; https://doi.org/10.1002/ptr.5653

12. J. Hao, X. Yang, X. L. Ding, L. M. Guo, C. H. Zhu, W. Ji, T. Zhou and X. Z. Wu, Paeoniflorin potentiates the inhibitory effects of erlotinib in pancreatic cancer cell lines by reducing ErbB3 phosphorylation, Sci. Rep. 6 (2016) 32809; https://doi.org/10.1038/srep32809

13. X. H. Nie, J. Ou-yang, Y. Xing, D. Y. Li, X. Y. Dong, R. E. Liu and R. X. Xu, Paeoniflorin inhibits human glioma cells via STAT3 degradation by the ubiquitin-proteasome pathway, Drug. Des. Devel. Ther. 9 (2015) 5611–5622; https://doi.org/10.2147/DDDT.S93912

14. H. Wang, H. Zhou, C. X. Wang, Y. S. Li, H. Y. Xie, J. D. Luo and Y. Zhou, Paeoniflorin inhibits growth of human colorectal carcinoma HT 29 cells in vitro and in vivo, Food Chem. Toxicol. 50 (2012) 1560–1567; https://doi.org/10.1016/j.fct.2012.01.035

15. Y. B. Zheng, G. C. Xiao, S. L. Tong, Y. Ding, Q. S. Wang, S. B. Li and Z. N. Hao, Paeoniflorin inhibits human gastric carcinoma cell proliferation through up-regulation of microRNA-124 and suppression of PI3K/Akt and STAT3 signaling, World J. Gastroenterol. 21 (2015) 7197–7207; https://doi.org/10.3748/wjg.v21.i23.7197

16. M. Y. Lin, S. Y. Chiang, Y. Z. Li, M. F. Chen, Y. S. Chen, J. Y. Wu and Y. W. Liu, Anti-tumor effect of Radix Paeoniae rubra extract on mice bladder tumors using intravesical therapy, Oncol. Lett. 12 (2016) 904–910; https://doi.org/10.3892/ol.2016.4698

17. J. Liang, F. Xu, Y. Z. Zhang., S. Huang, X. Y. Zang, X. Zhao, L. Zhang, M. Y. Shang, D. H. Yang, X. Wang and S. Q. Cai, The profiling and identification of the absorbed constituents and metabolites of Paeoniae radix rubra decoction in rat plasma and urine by the HPLC-DAD-ESI-IT-TOF-MS(n) technique: a novel strategy for the systematic screening and identification of absorbed constituents and metabolites from traditional Chinese medicines, J. Pharm. Biomed. Anal. 83 (2013) 108–121; https://doi.org/10.1016/j.jpba.2013.04.029

18. H. Wu, W. Li, T. Wang, Y. Shu and P. Liu, Paeoniflorin suppress NF-kappaB activation through modulation of I kappaB alpha and enhances 5-fluorouracil-induced apoptosis in human gastric carcinoma cells, Biomed. Pharmacother. 62 (2008) 659–666; https://doi.org/10.1016/j.biopha.2008.08.002

19. S. Fang, W. Zhu, Y. Zhang, Y. Shu and P. Liu, Paeoniflorin modulates multidrug resistance of a human gastric cancer cell line via the inhibition of NF-κB activation, Mol. Med. Rep. 5 (2012) 351–356; https://doi.org/10.3892/mmr.2011.652

20. H. Wang, H. Zhou, C. X. Wang, Y. S. Li, H. Y. Xie, J. D. Luo and Y. Zhou, Paeoniflorin inhibits growth of human colorectal carcinoma HT 29 cells in vitro and in vivo, Food. Chem. Toxicol. 50 (2012) 1560–1567; https://doi.org/10.1016/j.fct.2012.01.035

21. Z. D. Ge, A. W. Zhou, B. Wang, Y. X. Shen, C. H. Ding, A. P. Zhang, W. Wei and S. Y. Xu, Immunoregulatory effects of total glucosides of Paeony (TGP), Paeoniflorin (PF) and TGP removed PF on adjuvant arthritic rats, Chin. Pharmacol. Bull. 11 (1995) 303–305; https://doi.org/10.3321/j.issn:1001-1978.1995.04.012

22. Y. L. Zhu, L. Y. Wang, J. X. Wang, C. Wang, C. L. Wang, D. P. Zhao, Z. C. Wang and J. J. Zhang, Protective effects of paeoniflorin and albiflorin on chemotherapy-induced myelosuppression in mice, Chin. J. Nat. Med. 14 (2016) 599–606; https://doi.org/10.1016/S1875-5364(16)30070-X

23. S. Goldar, M. S. Khaniani, S. M. Derakhshan and B. Baradaran, Molecular mechanisms of apoptosis and roles in cancer development and treatment, Asian Pac. J. Cancer. Prev. 16 (2015) 2129–2144; https://doi.org/10.7314/APJCP.2015.16.6.2129

24. Z. Jin and W. S. El-Deiry, Overview of cell death signaling pathways, Cancer Biol. Ther. 4 (2005) 139–163; https://doi.org/10.4161/cbt.4.2.1508

25. S. Wang and W. Liu, Paeoniflorin inhibits proliferation and promotes apoptosis of multiple myeloma cells via its effects on microRNA-29b and matrix metalloproteinase-2, Mol. Med. Rep. 14 (2016) 2143–2149; https://doi.org/10.3892/mmr.2016.5498

26. N. Yang, H. Cui, F. Han, L. Zhang, T. Huang, Y. Zhou and J. Zhou, Paeoniflorin inhibits human pancreatic cancer cell apoptosis via suppression of MMP-9 and ERK signaling, Oncol. Lett. 12 (2016) 1471–1476; https://doi.org/10.3892/ol.2016.4761

27. Z. Zhou, S. Wang, C. Song and Z. Hu, Paeoniflorin prevents hypoxia-induced epithelial-mesenchymal transition in human breast cancer cells, Onco. Targets Ther. 9 (2016) 2511–2518; https://doi.org/10.2147/OTT.S102422

28. S. Hu, W. Sun, W. Wei, D. Wang, J. Jin, J. Wu, J. Chen, H. Wu and Q. Wang, Involvement of the prostaglandin E receptor EP2 in paeoniflorin-induced human hepatoma cell apoptosis, Anticancer Drugs. 24 (2013) 140–149; https://doi.org/10.1097/CAD.0b013e32835a4dac

29. H. Yu and R. Jove, The STATs of cancer--new molecular targets come of age, Nat. Rev. Cancer. 4 (2004) 97–105; https://doi.org/10.1038/nrc1275

30. P. K. Epling-Burnette, J. H. Liu, R. Catlett-Falcone, J. Turkson, M. Oshiro, R. Kothapalli, Y. Li, J. M. Wang, H. F.Yang-Yen, J. Karras, R. Jove and T. P. Jr. Loughran, Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression, J. Clin. Invest. 107 (2001) 351–362; https://doi.org/10.1172/JCI9940

Acta Pharmaceutica

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