Down-regulation of COX-2 and hTERT Expression by Healthful Decoction Utilizing Phellinus Linteus in Human Lung Carcinoma Cells

상황을 이용한 한의학적 보건기능 개선제에 의한 인체폐암세포의 증식억제에 관한 연구

  • Park Cheol (Department of Biochemistry, College of Natural Sciences, Dongeui University) ;
  • Lee Yong Tae (Department of Physiology, College of Natural Sciences, Dongeui University) ;
  • Jeong Young Kee (Department of Microbiology, College of Natural Sciences, Dongeui University) ;
  • Choi Byung Tae (Department of Anatomy, Dongeui University College of Oriental Medicine and Research Institute of Oriental Medicine) ;
  • Lee Sang Hyeon (Department of Bioscience and Biotechnology, Silla University) ;
  • Choi Yung Hyun (Department of Biochemistry, College of Natural Sciences, Dongeui University)
  • 박철 (동의대학교 한의과대학 생화학교실) ;
  • 이용태 (동의대학교 한의과대학 생리학교실) ;
  • 정영기 (동의대학교 자연과학대학 미생물학과) ;
  • 최병태 (동의대학교 한의과대학 해부학교실 및 한의학연구소) ;
  • 이상현 (신라대학교 생명공학과) ;
  • 최영현 (동의대학교 한의과대학 생화학교실)
  • Published : 2004.04.01

Abstract

The objective of the present study was to investigate the effects of aqueous extract from the healthful decoction utilizing Phellinus linteus (HDPL) on the growth of human lung carcinoma A549 cells. HDPL treatment declined the cell viability of A549 cells in a concentration-dependent manner and the anti-proliferative effects by HDPL treatment were associated with morphological changes such as membrane shrinking and cell rounding up. HDPL treatment did not affect the distribution of the cell cycle. Western blot analysis and RT-PCT data revealed that the levels of tumor suppressor p53 and cyclin-dependent kinase inhibitor p21WAF1/CIP1 in HDPL-treated A549 cells were remained unchanged. However, HDPL treatment inhibited the expression of cyclooxygenase-2 (COX-2) mRNA and protein in a concentration-dependent fashion. Additionally, the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, was progressively down-regulated by HDPL treatment. Taken together, these findings suggest that HDPL-induced inhibition of human lung cancer cell proliferation is associated with the inhibition of several major growth regulatory gene products, such as COX-2 and hTERT, and HDPL may have therapeutic potential in human lung cancer.

Keywords

References

  1. Gann v.59 Antitumor activity of some basidiomycetes. especially Phellinus linteus. Ikekawa, T.; Nakanish, M.; Uehara, N.; Chihara, G.; Fukuoka, E.
  2. Food Rev. Int. v.11 Agaricus blazei Murill: medicinal and dietry effects. Mizuno, T.; Kawariharatake https://doi.org/10.1080/87559129509541026
  3. Kor. J. Food Sci. Technol. v.32 In vitro and in vivo antitumor activity of the fruit body of Phellinus linteus. Lee, K.Y.; Han, M.J.; Park, S.Y.; Kim, D.H.
  4. Carcinogenesis v.23 The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide. Cho, J.H.; Cho, S.D.; Hu, H.; Kim, S.H.; Lee, S.K.; Lee, Y.S.; Kang, K.S. https://doi.org/10.1093/carcin/23.7.1163
  5. Kor. J. Oriental Physiol. Pathol. v.16 Study on antitumor and immunomodulatory effects of Cambodian Phellinus linteus Lee, H.J.; Lee, H.J.; Park, J.M.; Song, G.Y.; Kang, K.S.; Kim, S.H.
  6. J. Kor. Soc. Food Sci. Nutr. v.29 Antimutagenic and cytotoxicity effects of Phellinus linteus extracts. Ji, J.H.; Kim, M.N.; Chung, C.K.; Ham, S.S.
  7. J. Fd. Hyg. Safety v.13 Effects of artificially cultured Phellinus linteus on harmful intestinal bacterial enzymes and rat intestinal $\beta$-glucocidases. Kim, D.H.; Choi, H.J.; Bae, E.A.
  8. Arch. Pharm. Res. v.15 Immunostimulating activity of Phellinus linteus extracts to B-lymphocyte. Oh, G.T.; Han, S.B.; Kim, H.M.; Han, M.W.; Yoo, I.D.
  9. Int. J. Immunopharm. v.18 Stimulation of hormoral and cell mediated immunity by polysaccharide from mushroom Phellinus linteus. Kim, H.M.; Han, S.B.; Oh, G.T.; Kim, Y.H.; Hong, D.H.; Hong, N.D.; Yoo, I.D. https://doi.org/10.1016/0192-0561(96)00028-8
  10. J. Applied Pharmacol. v.9 Effects of Phellinus linteus extracts on the hormonal immune response in normal and cyclophosphamide-treated mice. Pyo, M.Y.; Hyun, S.M.; Yang, K.S.
  11. Carbohydr. Res. v.189 Fractionation and antitumor activity of the water-insoluble residue of Agaricus blazei fruiting bodies. Kawagishi, H.; Inagaki, R.; Kanao, T.; Mizuno, T
  12. Nippon Shokuhin Kagaku Kogaku Kaishi v.45 Tumoricidal activity of high molecular weight polysaccharides derived from Agaricus blazei via oral administration in the mouse tumor model. Fujimiya, Y.; Kobori, H.; Oshiman, K.; Soda, R.; Ebina, T. https://doi.org/10.3136/nskkk.45.246
  13. Food Sci. Biotechnol. v.10 In vitro and in vivo antitumor activities of water extracts from Agaricus blazei Murill. Chun, H.S.; Choi, E.H.; Kim, H.J.; Choi, C.W.; Hwang, S.J.
  14. Kor. J. Food Sci. Technol. v.32 Antimutagenic and cytotoxicity effects of Agaricus blazei extracts. Ji, J.H.; Kim, M.N.; Choi, K.P.; Chung, C.K.; Ham, S.S.
  15. Kor. J. Oriental Physiol. Pathol. v.18 The effects of healthful decoction utilizing Phellinus linteus in carbon tetrachloride-injected rats. Kang, K.H.; Lee, J.H.; Choi, Y.H.; Choi, B.T.; Lee, Y.T.
  16. J. Biol. Chem. v.272 Regulation of cyclin D1 by calpain protease. Choi, Y.H.;Lee, S.J.;Nguyen, P.; Jang, J.S.; Lee, J.; Wu, M.; Takano, E.; Maki, M.; Henkart, P.; Trepel, J.B. https://doi.org/10.1074/jbc.272.45.28479
  17. Int. J. Oncol. v.23 Induction of Bax and activation of caspases during $\beta$-sitosterol-mediated apoptosis in human colon cancer cells. Choi, Y.H.; Kong, K.R.; Kim, Y.A.; Jung, K.O.; Kil, J.H.; Rhee, S.H.; Park, K.Y.
  18. Cancer Res. v.60 The Pezcoller lecture: cancer cell cycles revisited. Sherr, C.J.
  19. Cell v.81 The retinoblastoma protein and cell cycle control. Weinberg, R.A. https://doi.org/10.1016/0092-8674(95)90385-2
  20. Curr. Opin. Cell Biol. v.6 Cdk inhibitors: on the threshold of checkpoints and development. Elledge, S.J.; Harper, J.W. https://doi.org/10.1016/0955-0674(94)90055-8
  21. Cell v.75 The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Harper, J.W.; Adami, G.R.; Wei, N.; Keyomarsi, K.; Elledge, S.J. https://doi.org/10.1016/0092-8674(93)90499-G
  22. Cancer Res. v.54 WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. El-Deiry, W.S.; Harper, J.W.; O'Connor, P.M.; Velculescu, V.E.; Canman, C.E.; Jackman, J.; Pietenpol, J.A.; Burrell, M.; Hill, D.E.; Wang, Y.; Wiman, K.G.; Mercer, W.E.; Kastan, M.B.; Kohn, K.W.; Elledge, S.J.; Kinzler, K.W.; Vogelstain, B.
  23. Cell v.80 Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Miyashita, T.; Reed, J.C. https://doi.org/10.1016/0092-8674(95)90412-3
  24. Nature v.366 p21 is a universal inhibitor of cyclin kinases. Xiong, Y.; Hannon, G.; Zhang, H.; Casso, D.; Kobayashi, R.; Beach, D. https://doi.org/10.1038/366701a0
  25. Cell Biol. Int. v.17 Multiple pathways to apoptosis. Evans, V.G. https://doi.org/10.1006/cbir.1993.1087
  26. Best Pract. Res. Clin. Gastroenterol. v.15 COX-2 inhibition and prevention of cancer. Giercksky, K.E. https://doi.org/10.1053/bega.2001.0237
  27. Int. J. Cancer v.94 Is COX-2 inhibition a panacea for cancer prevention? Vainio, H.
  28. J. Cancer Res. Clin. Oncol. v.127 Cyclooxygenase-2: a novel target for cancer chemotherapy? Dempke, W.; Rie, C.; Grothey, A.; Schmoll, H.J. https://doi.org/10.1007/s004320000225
  29. Mutat. Res. v.480 Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-$\kappa$B activation. Surh, Y.J.; Chun, K.S.; Cha, H.H.; Han, S.S.; Keum, Y.S.; Park, K.K.; Lee, S.S. https://doi.org/10.1016/S0027-5107(01)00183-X
  30. Lab. Invest. v.79 Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Sawaoka, H.; Tsuji, S.; Tsujii, M.; Gunawan, E.S.; Sasaki, Y.;Kawano, S.; Hori, M.
  31. J. Clin. Invest. v.107 Therapeutic potential of inhibition of the NF-$\kappa$B pathway in the treatment of inflammation and cancer. Yamamoto, Y.; Gaynor, R.B. https://doi.org/10.1172/JCI11914
  32. Gene v.269 Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT) Poole, J.C.; Andrews, L.G.; Tollefsbol, T.O. https://doi.org/10.1016/S0378-1119(01)00440-1
  33. Oncogene v.21 Complex regulatory mechanisms of telomerase activity in normal and cancer cells: How can we apply them for cancer therapy. Kyo, S.; Inoue, M. https://doi.org/10.1038/sj.onc.1205163
  34. EMBO J. v.16 ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase. Vaziri, H.; West, M.D.; Allsopp, R.C.; Davison, T.S.; Wu, Y.S.; Arrowsmith, C.H.; Poirier, G.G.; Benchimol, S. https://doi.org/10.1093/emboj/16.19.6018
  35. Br. J. Cancer v.85 DNA damage-induced cell cycle checkpoints involve both p53-dependent and -independent pathways: role of telomere repeat binding factor 2. Narayan, S.; Jaiswal, A.S.; Multani, A.S.; Pathak, S. https://doi.org/10.1054/bjoc.2001.2002
  36. An update. Mutat. Res. v.462 Telomeres, telomerase, and myc. Cerni, C. https://doi.org/10.1016/S1383-5742(99)00091-5