Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Meclofenamate Suppresses MUC5AC Mucin Gene Expression by Regulating the NF-kB Signaling Pathway in Human Pulmonary Mucoepidermoid NCI-H292 Cells

  • Jiho Ryu (Department of Pharmacy, College of Pharmacy, Chungbuk National University) ;
  • Kyung-il Kim (Department of Pharmacology, School of Medicine, Chungnam National University) ;
  • Rajib Hossain (Department of Pharmacology, School of Medicine, Chungnam National University) ;
  • Misoon Lee (Department of Pharmacy, College of Pharmacy, Chungbuk National University) ;
  • Jin Tae Hong (Department of Pharmacy, College of Pharmacy, Chungbuk National University) ;
  • Hyun Jae Lee (Smith Liberal Arts College and Department of Addiction Science, Graduate School, Sahmyook University) ;
  • Choong Jae Lee (Department of Pharmacology, School of Medicine, Chungnam National University)
  • Received : 2023.02.21
  • Accepted : 2023.03.13
  • Published : 2023.05.01
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Abstract

The current study aimed to reveal the potential effect of meclofenamate, a nonsteroidal anti-inflammatory drug, on the gene expression of airway MUC5AC mucin. Human pulmonary mucoepidermoid NCI-H292 cells were pretreated with meclofenamate for 30 min and stimulated with phorbol 12-myristate 13-acetate (PMA) for 24 h. Thereafter, the effect of meclofenamate on the PMA-induced nuclear factor kappa B (NF-kB) signaling pathway was assessed. Meclofenamate inhibited glycoprotein production and mRNA expression of MUC5AC mucins induced by PMA by inhibiting the degradation of inhibitory kappa Bα (IkBα) and NF-kB p65 nuclear translocation. These results suggest meclofenamate suppresses mucin gene expression by regulating NF-kB signaling pathway in human pulmonary epithelial cells.

Keywords

Acknowledgement

This research was supported by the NRF-2014R1A6A 1029617 Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education.

References

  1. Adler, K. B. and Li, Y. (2001) Airway epithelium and mucus: intracellular signaling pathways for gene expression and secretion. Am. J. Respir. Cell Mol. Biol. 25, 397-400. https://doi.org/10.1165/ajrcmb.25.4.f214
  2. Chen, H., Jia, B., Zhang, Q. and Zhang, Y. (2022) Meclofenamic acid restores gefinitib sensitivity by downregulating breast cancer resistance protein and multidrug resistance protein 7 via FTO/m6A-demethylation/c-Myc in non-small cell lung cancer. Front. Oncol. 12, 870636.
  3. Cho, Y., Vermeire, J. J., Merkel, J. S., Leng, L., Du, X., Bucala, R., Cappello, M. and Lolis, E. (2011) Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors. Chem. Biol. 18, 1089-1101. https://doi.org/10.1016/j.chembiol.2011.07.011
  4. Choi, B. S., Kim, Y. J., Choi, J. S., Lee, H. J. and Lee, C. J. (2019) Obtusifolin isolated from the seeds of Cassia obtusifolia regulates the gene expression and production of MUC5AC mucin in airway epithelial cells via affecting NF-κB pathway. Phytother. Res. 33, 919-928. https://doi.org/10.1002/ptr.6284
  5. Choi, B. S., Kim, Y. J., Yoon, Y. P., Lee, H. J. and Lee, C. J. (2018) Tussilagone suppressed the production and gene expression of MUC5AC mucin via regulating nuclear factor-kappa B signaling pathway in airway epithelial cells. Korean J. Physiol. Pharmacol. 22, 671-677. https://doi.org/10.4196/kjpp.2018.22.6.671
  6. Conroy, M. C., Randinitis, E. J. and Turner, J. L. (1991) Pharmacology, pharmacokinetics, and therapeutic use of meclofenamate sodium. Clin. J. Pain 7, S44-S48. https://doi.org/10.1097/00002508-199108000-00007
  7. Ellis, C. N., Goldfarb, M. T., Roenigk, H. H., Jr., Rosenbaum, M., Wheeler, S. and Voorhees, J. J. (1986) Effects of oral meclofenamate therapy in psoriasis. J. Am. Acad. Dermatol. 14, 49-52. https://doi.org/10.1016/S0190-9622(86)70006-6
  8. Fujisawa, T., Velichko, S., Thai, P., Hung, L. Y., Huang, F. and Wu, R. (2009) Regulation of airway MUC5AC expression by IL-1beta and IL-17A; the NF-kappa B paradigm. J. Immunol. 183, 6236-6243. https://doi.org/10.4049/jimmunol.0900614
  9. Garvin, L. M., Chen, Y., Damsker, J. M. and Rose, M. C. (2016) A novel dissociative steroid VBP15 reduces MUC5AC gene expression in airway epithelial cells but lacks the GRE mediated transcriptional properties of dexamethasone. Pulm. Pharmacol. Ther. 38, 17-26. https://doi.org/10.1016/j.pupt.2016.04.004
  10. Hill, J. and Zawia, N. H. (2021) Fenamates as potential therapeutics for neurodegenerative disorders. Cells 10, 702.
  11. Ishinaga, H., Takeuchi, K., Kishioka, C., Suzuki, S., Basbaum, C. and Majima, Y. (2005) Pranlukast inhibits NF-kappaB activation and MUC2 gene expression in cultured human epithelial cells. Pharmacology 73, 89-96. https://doi.org/10.1159/000081294
  12. Kim, E. J., Yoon, Y. P., Woo, K. W., Kim, J. H., Min, S. Y., Lee, H. J., Lee, S. K., Hong, J. H., Lee, K. R. and Lee, C. J. (2016) Verticine, ebeiedine and suchengbeisine isolated from the bulbs of Fritillaria thunbergii Miq. inhibited the gene expression and production of MUC5AC mucin from human airway epithelial cells. Phytomedicine 23, 95-104. https://doi.org/10.1016/j.phymed.2015.12.016
  13. Kim, J. O., Sikder, M. A., Lee, H. J., Rahman, M., Kim, J. H., Chang, G. T. and Lee, C. J. (2012) Phorbol ester or epidermal growth factor-induced MUC5AC mucin gene expression and production from airway epithelial cells are inhibited by apigenin and wogonin. Phytother. Res. 26, 1784-1788. https://doi.org/10.1002/ptr.4650
  14. Kurakula, K., Hamers, A. A., van Loenen, P. and de Vries, C. J. (2015) 6-Mercaptopurine reduces cytokine and Muc5ac expression involving inhibition of NF-kB activation in airway epithelial cells. Respir. Res. 16, 73.
  15. Laos, S., Baeckstrom, D. and Hansson, G. C. (2006) Inhibition of NF-kappaB activation and chemokine expression by the leukocyte glycoprotein, CD43, in colon cancer cells. Int. J. Oncol. 28, 695-704.
  16. Lee, H. J., Park, J. S., Yoon, Y. P., Shin, Y. J., Lee, S. K., Kim, Y. S., Hong, J. H., Son, K. H. and Lee, C. J. (2015) Dioscin and methylprotodioscin isolated from the root of Asparagus cochinchinensis suppressed the gene expression and production of airway MUC5AC mucin induced by phorbol ester and growth factor. Phytomedicine 22, 568-572. https://doi.org/10.1016/j.phymed.2015.03.009
  17. Li, J. D., Dohrman, A. F., Gallup, M., Miyata, S., Gum, J. R., Kim, Y. S., Nadel, J. A., Prince, A. and Basbaum, C. B. (1997) Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc. Natl. Acad. Sci. U. S. A. 94, 967-972. https://doi.org/10.1073/pnas.94.3.967
  18. Li, X., Jin, F., Lee, H. J. and Lee, C. J. (2020) Recent advances in the development of novel drug candidates for regulating the secretion of pulmonary mucus. Biomol. Ther. (Seoul) 28, 293-301. https://doi.org/10.4062/biomolther.2020.002
  19. Lillehoj, E. R. and Kim, K. C. (2002) Airway mucus: its components and function. Arch. Pharm. Res. 25, 770-780. https://doi.org/10.1007/BF02976990
  20. Rogers, D. F. (2007) Mucoactive agents for airway mucus hypersecretory diseases. Respir. Care 52, 1176-1193.
  21. Rose, M. C. and Voynow, J. A. (2006) Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol. Rev. 6, 245-278. https://doi.org/10.1152/physrev.00010.2005
  22. Ryu, J., Lee, H. J., Park, S. H., Kim, J., Lee, D., Lee, S. K., Kim, Y. S., Hong, J. H., Seok, J. H. and Lee, C. J. (2014) Effects of the root of Platycodon grandiflorum on airway mucin hypersecretion in vivo and platycodin D(3) and deapi-platycodin on production and secretion of airway mucin in vitro. Phytomedicine 21, 529-533. https://doi.org/10.1016/j.phymed.2013.10.004
  23. Ryu, J., Lee, H. J., Park, S. H., Sikder, M. A., Kim, J. O., Hong, J. H., Seok, J. H. and Lee, C. J. (2013) Effect of prunetin on TNF-α-induced MUC5AC mucin gene expression, production, degradation of IκB and translocation of NF-κB p65 in human airway epithelial cells. Tuberc. Respir. Dis. (Seoul) 75, 205-209. https://doi.org/10.4046/trd.2013.75.5.205
  24. Saglam, B. S., Kanli, A., Yanar, S., Kasap, M. and Akpinar, G. (2022) Investigation of the effect of meclofenamic acid on the proteome of LNCaP cells reveals changes in alternative polyadenylation and splicing machinery. Med. Oncol. 39, 190.
  25. Seo, H. S., Sikder, M. A., Lee, H. J., Ryu, J. and Lee, C. J. (2014) Apigenin inhibits tumor necrosis factor-α-induced production and gene expression of mucin through regulating nuclear factor-kappa B signaling pathway in airway epithelial cells. Biomol. Ther. (Seoul) 22, 525-531. https://doi.org/10.4062/biomolther.2014.094
  26. Shao, M. X., Ueki, I. F. and Nadel, J. A. (2003) TNF-alpha converting enzyme mediated MUC5AC mucin expression in cultured human airway epithelial cells. Proc. Natl. Acad. Sci. U. S. A. 100, 11618-11623. https://doi.org/10.1073/pnas.1534804100
  27. Sikder, M. A., Lee, H. J., Mia, M. Z., Park, S. H., Ryu, J., Kim, J. H., Min, S. Y., Hong, J. H., Seok, J. H. and Lee, C. J. (2014) Inhibition of TNF-α-induced MUC5AC mucin gene expression and production by wogonin through the inactivation of NF-κB signaling in airway epithelial cells. Phytother. Res. 28, 62-68. https://doi.org/10.1002/ptr.4954
  28. Sprenger, L., Goldmann, T., Vollmer, E., Steffen, A., Wollenberg, B., Zabel, P. and Hauber, H. P. (2011) Dexamethasone and N-acetylcysteine attenuate Pseudomonas aeruginosa-induced mucus expression in human airways. Pulm. Pharmacol. Ther. 24, 232-239. https://doi.org/10.1016/j.pupt.2010.11.003
  29. Takeyama, K., Dabbagh, K., Lee, H., Agusti, C., Lausier, J. A., Ueki, I. F., Grattan, K. M. and Nadel, J. A. (1999) Epidermal growth factor system regulates mucin production in airways. Proc. Natl. Acad. Sci. U. S. A. 96, 3081-3086. https://doi.org/10.1073/pnas.96.6.3081
  30. Velosa, J. A., Torres, V. E., Donadio, J. V., Jr., Wagoner, R. D., Holley, K. E. and Offord, K. P. (1985) Treatment of severe nephrotic syndrome with meclofenamate: an uncontrolled pilot study. Mayo Clin. Proc. 60, 586-592. https://doi.org/10.1016/S0025-6196(12)60980-X
  31. Voynow, J. A. and Rubin, B. K. (2009) Mucins, mucus, and sputum. Chest 135, 505-512. https://doi.org/10.1378/chest.08-0412
  32. Wu, D. Y., Wu, R., Reddy, S. P., Lee, Y. C. and Chang, M. M. (2007) Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate. Am. J. Pathol. 170, 20-32. https://doi.org/10.2353/ajpath.2007.060452
  33. Yanar, S., Kasap, M., Kanli, A., Akpinar, G. and Sarihan, M. (2022) Proteomics analysis of meclofenamic acid-treated small cell lung carcinoma cells revealed changes in cellular energy metabolism for cancer cell survival. J. Biochem. Mol. Toxicol. e23289. doi: 10.1002/jbt.23289 [Online ahead of print].