Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Honokiol Inhibits Nitric Oxide-Induced Apoptosis in Rabbit Articular Chondrocytes via PI-3K/AKT Pathway

Honokiol에 의한 토끼의 무릎 연골세포에서 PI-3K/AKT pathway를 통하여 nitric oxide에 의해 유도되는 세포사멸의 억제

  • Lee, Won-Kil (Department of Biological Sciences, College of Natural Sciences, Kongju National University) ;
  • Kim, Song-Ja (Department of Biological Sciences, College of Natural Sciences, Kongju National University)
  • 이원길 (공주대학교 자연과학대학 생명과학과) ;
  • 김송자 (공주대학교 자연과학대학 생명과학과)
  • Received : 2010.07.29
  • Accepted : 2010.10.09
  • Published : 2010.10.30
Download PDF
⟨ Previous Next ⟩

Abstract

Honokiol is a small molecular weight ligand originally isolated from the Chinese medicinal herb Magnolia officinalis, a plant used in traditional Chinese and Japanese medicine [9]. In a previous study, the effects of honokiol were shown to have anti-angiogenic, anti-invasive and anti-proliferative activities in a variety of cancers [1,3,4,11,13,17,24,29,30]. We showed previously that direct production of nitric oxide (NO) by treatment of NO donor, sodium nitroprusside (SNP), led to apoptosis in rabbit articular chondrocytes [15,16]. This study confirmed that NO-induced apoptosis was suppressed by honokiol treatment in a dose-dependent manner as determined by cell phenotype, MTT assay, Western blot analysis and FACS analysis in articular chondrocytes. Treatment of honokiol inhibited SNP-induced expression of p53 as well as DNA fragmentation in articular chondrocytes, but increased expressionof pro-caspase-3. Inhibition of SNP-induced apoptosis by honokiol treatment was rescued by LY294002, the specific inhibitors of phosphoinositide 3-kinase (PI-3K) in articular chondrocytes. Our results indicate that honokiol inhibits NO-induced apoptosis via PI-3K/AKT pathway in rabbit articular chondrocytes.

Honokiol은 작은 분자량을 갖는 중국의 약초인 'Magnolia officinalis'에서 추출한 리간드로서 중국과 일본에서 전통 의약제로 사용되어 왔다. 이전 연구에서는 honokiol이 다양한 종류의 암에서anti-angiogenic, anti-invasive, anti-proliferative activities 등의 다양한 효과가 있는 것으로 알려져 있다. 우리는 이전 연구에서 Nitric oxide donor인 sodium nitroprusside (SNP)에 의해서 토끼 무릎관절연골세포에서 세포사멸이 일어나는 것을 보고하였다. 본 연구에서는 무릎 연골세포에서 NO에 의해 유도되는 세포사멸이 honokiol 처리농도에 의존적으로 억제되는 것을 세포형태, MTT assay, Western blot analysis 그리고 FACS를 통해 확인할 수 있었다. 또한, honokiol은 SNP에 의해 유도되는 p53의 발현 및 pro-caspase-3의 활성 저해, DNA fragmentation을 억제하였다. Honokiol에 의한 세포사멸 억제는 PI-3K의 특정 저해제인 LY294002를 SNP와 honokiol과 함께 처리하였을 때 세포의 사멸이 증가하는 것을 확인할 수 있었다. 이는 honokiol이 PI-3K/AKT pathway를 통하여 NO가 유도하는 세포사멸을 억제하는 것을 의미한다.

Keywords

References

  1. Ahn, K. S., G. Sethi, S. Shishodia, B. Sung, J. L. Arbiser, and B. B. Aggarwal. 2006. Honokiol potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through modulation of nuclear factor-kappaB activation pathway. Mol. Cancer Res. 4,621-633. https://doi.org/10.1158/1541-7786.MCR-06-0076
  2. Amin, A. R and S. B. Abramson. 1998. The role of nitric oxide in articular cartilage breakdown in osteoarthritis. Curr. Opin. Rheumatol. 10, 263-268. https://doi.org/10.1097/00002281-199805000-00018
  3. Bai,X., F. Cerimele, and M. Ushio-Fukai. 2003. Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J. Biol. Chem. 278, 35501-35507. https://doi.org/10.1074/jbc.M302967200
  4. Battle, T. E., J. Arbiser, and D. A. Frank. 2005. The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Blood 106, 690-697. https://doi.org/10.1182/blood-2004-11-4273
  5. Blancco,F, J., R. Guitian, E. Vazquez-Martul, F. J. de Toro, and F. Galdo. 1998. Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology. Arthritis Rheum. 41, 284-289. https://doi.org/10.1002/1529-0131(199802)41:2<284::AID-ART12>3.0.CO;2-T
  6. Cao, M., A. westerhausen-Larson, C. Niyibizi, K. Kavalkovich, H. I. Georgescu, C. F. Rizzo, P. A. Hebda, M. Stefanovic-Racic, and C. H. Evans. 1997. Nitric oxide inhibits the synthesis of type-II collagen without altering Col2A1 mRNA abundance: prolyl hydroxylase as a possible target. Biochem. J. 324, 305-310.
  7. Choy, E. H., and G. S. Panayi. 2002. Cytokine pathways and joint inflammation in rheumatoid arthritis. N. Engl. J. Med. 344, 907-916. https://doi.org/10.1056/NEJM200103223441207
  8. Fong, W. F., A. K. Tse, K. H. Poon, and C. Wang. 2005. Magnolol and honokiol enhance HL-60 human leukemia cell differentiation induced by 1,25-dihydroxyvitamin D3 and retinoic acid. Int. J. Biochem. Cell Bio.l 37, 427-441. https://doi.org/10.1016/j.biocel.2004.05.021
  9. Fujita, M., H. Itokawa, and Y. Sashida. 1973. Studies on the componets of Magnolia obovata Thunb II${\pm}$on the components of the methanol extrct of the bark. Yakugaku Zasshi 93, 422-428.
  10. Hashimoto, S., R. L. Oches, S. Komiya, and M. Lotz. 1998. Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis Rheum. 41, 1632-1638. https://doi.org/10.1002/1529-0131(199809)41:9<1632::AID-ART14>3.0.CO;2-A
  11. Hibasami, H., Y. Achiwa, and H. Katsuzakil. 1998. Honokiol induces apoptosis in human lymphoid leukemia Molt 4B cells. Int. J. Mol. Med. 2, 671-673.
  12. Im, J. H. and S. J. Kim. 2010. Paclitaxel induced caspase-independent mitotic catastrophe in rabbit articular chondrocyte. J. Life Sci. 20, 519-527 https://doi.org/10.5352/JLS.2010.20.4.519
  13. Ishitsuka, K., T. Hideshima, and M. Hamasaki. 2005. Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and-independent apoptosis. Blood 106, 1794-1800. https://doi.org/10.1182/blood-2005-01-0346
  14. Kim, S. J., H. G. Kim, C. D. Oh, Y. M. Yoon, W. K. Song, J. H. Kim, Y. J. Yoo, O. S. Bang, S. S. Kang, and J. S. Chun. 2002. p38 kinase-dependent and -independent Inhibition of protein kinase C zeta and -alpha regulates nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes. J. Biol. Chem. 277, 30375-30381. https://doi.org/10.1074/jbc.M205193200
  15. Kim, S. J., J. W. Ju, C. D. Oh, Y. M. Yoon, W. K. Song, J. H. Kim, Y. J. Yoo, O. S. Bang, S. S. Kang, and J. S. Chun. 2002. ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. J. Biol. Chem. 277, 1332-1339. https://doi.org/10.1074/jbc.M107231200
  16. Kim, S. J., S. G. Hwang, D. Y. Shin, S. S. Kang, and J. S. Chun. 2002. p38 kinase regulates nitric oxide-induced apoptosis ofarticular chondrocytes by accumulating p53 via NFkappa B-dependent transcription and stabilization by serine 15 phosphorylation. J. Biol. Chem. 277, 33501-33508. https://doi.org/10.1074/jbc.M202862200
  17. Konoshima, T., M. Kozuka, and H. Tokuda. 1991. Studies on inhibitors of skin tumor promotion, IX. Neolignans from Magnolia officinalis. J. Natural Products 54, 816-822. https://doi.org/10.1021/np50075a010
  18. Liou, K. T., S. M. Lin, S. S. Huang, C. L. Chih, and S. K. Tsai. 2003. Honokiol ameliorates cerebral infarction from ischemia- reperfusion injury in rats. Planta Med. 69, 130-134. https://doi.org/10.1055/s-2003-37707
  19. Liou, K. T., Y. C. Shen, C. F. Chen, C. M. Tsao, and S. K. Tsai. 2003. The anti-inflammatory effect of honokiol on neutrophils: mechanisms in the inhibition of reactive oxygen species production. Eur. J. Pharmacol. 475, 19-27. https://doi.org/10.1016/S0014-2999(03)02121-6
  20. Lo, Y. C., C. M. Teng, C. F. Chen, C. C. Chen, and C. Y. Hong. 1994. Magnolol and honokiol isolated from Magnolia officinalis protect rat heart mitochondria against lipid peroxidation. Biochem. Pharmacol. 9, 549-553.
  21. Martel-Pelletier, J., N. Alaaeddine, and J. P. Pelletier. 1999. Cytokines and their role in the pathophysiology of osteoarthritis. Front. Biosci. 4, 694-703. https://doi.org/10.2741/Martel
  22. Oh,C. D., S. H. Chang, Y. M. Yoon, S. J. Lee, Y. S. Lee, S. S. Kang, and J. S. Chun. 2000. Opposing role of mitogen-activated protein kinase subtypes, Erk-1/2 and p38, in the regulation of chondrogenesis of mesenchymes. J. Biol. Chem. 275, 5613-5619. https://doi.org/10.1074/jbc.275.8.5613
  23. Sandell, L. J. and T. Aigner. 2001. Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis. Arthritis Res. 3, 107-113. https://doi.org/10.1186/ar148
  24. Shigemura, K., J. L. Arbiser, and S. Y. Sun. 2007. Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells. Cancer 109, 1279-1289. https://doi.org/10.1002/cncr.22551
  25. Taskiran, D., M. Stefanovic-Racic, H. Georgescu, and C. Evans. 1994. Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1. Biochem. Biophys. Res. Commun. 200, 142-148. https://doi.org/10.1006/bbrc.1994.1426
  26. Teng, C. M., C. C. Chen, F. N. Ko, L. G. Lee, T. F. Huang, Y. P. Chen, and H. Y. Hsu. 1988. Two antiplatelet agents from Magnolia officinalis. Thromb Res. 50, 757-765. https://doi.org/10.1016/0049-3848(88)90336-2
  27. Wang, T. , F. Chen, Z. Chen, Y. F. Wu, X. L. Xu, S. Zheng, and X. Hu. 2004. Honokiol induces apoptosis through p53-independent pathway in human colorectal cell line RKO. World J. Gastroenterol. 10, 2205-2208.
  28. Watanabe, K., H. Watanabe, Y. Goto, M. Yamaguchi, N. Yamamoto, and K. Hagino. 1983. Pharmacological properties of magnolol and honokiol extracted from Magnolia officinalis: central depressant effects. Planta Med. 49, 103-108. https://doi.org/10.1055/s-2007-969825
  29. Wolf, I., J. O'Kelly, and N. Wakimoto. 2007. Honokiol, a natural biphenyl, inhibits in vitro and in vivo growth of breast cancer through induction of apoptosis and cell cycle arrest. Int. J. Oncol. 30, 1529-1537.
  30. Yang, S. E., M. T. Hsieh, T. H. Tsai, and S. L. Hsu. 2002. Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells. Biochem. Pharmacol. 63, 1641-1651. https://doi.org/10.1016/S0006-2952(02)00894-8
  31. Yatsugi, N., T. Tsukazaki, M. Osaki, T. Koji, S. Yamashita, and H. Shindo. 2000. Apoptosis of articular chondrocytes in rheumatoid arthritis and osteoarthritis: correlation of apoptosis with degree of cartilage destruction and expression of apoptosis-related proteins of p53 and c-myc. J. Orthop. Sci. 5, 150-156. https://doi.org/10.1007/s007760050142
  32. Yoon, Y. M., S. J. Kim, C. D. Oh, J. W. Ju, W. K. Song, Y. J. Yoo, T. L. Huh, and J. S. Chun. 2002. Maintenance of differentiated phenotype of articular chondrocytes by protein kinase C and extracellular signal-regulated protein kinase. J. Biol. Chem. 277, 8412-8420. https://doi.org/10.1074/jbc.M110608200