Please use this identifier to cite or link to this item:
Expression of tumor-associated NADH oxidase (tNOX) affects capsaicin-induced growth inhibition in gastric cancer cells
|關鍵字:||gastric cancer;胃癌;tNOX;apoptosis;capsaicin;辣椒素;凋亡;生長抑制||出版社:||生物醫學研究所||引用:||1. Brightman, A.O., Wang, J., Miu, R.K., Sun, I.L., Barr, R., Crane, F.L. and Morre, D.J. (1992) A growth factor- and hormone-stimulated NADH oxidase from rat liver plasma membrane. Biochim Biophys Acta, 1105, 109-117. 2. Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D. and Julius, D. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature, 389, 816-824. 3. Chen, G. and Goeddel, D.V. (2002) TNF-R1 signaling: a beautiful pathway. Science, 296, 1634-1635. 4. Chueh, P.J., Wu, L.Y., Morre, D.M. and Morre, D.J. (2004) tNOX is both necessary and sufficient as a cellular target for the anticancer actions of capsaicin and the green tea catechin (-)-epigallocatechin-3-gallate. Biofactors, 20, 235-249. 5. Hail, N., Jr. and Lotan, R. (2009) Cancer chemoprevention and mitochondria: targeting apoptosis in transformed cells via the disruption of mitochondrial bioenergetics/redox state. Mol Nutr Food Res, 53, 49-67. 6. Huang, S.P., Chen, J.C., Wu, C.C., Chen, C.T., Tang, N.Y., Ho, Y.T., Lo, C., Lin, J.P., Chung, J.G. and Lin, J.G. (2009) Capsaicin-induced apoptosis in human hepatoma HepG2 cells. Anticancer Res, 29, 165-174. 7. Ito, K., Nakazato, T., Yamato, K., Miyakawa, Y., Yamada, T., Hozumi, N., Segawa, K., Ikeda, Y. and Kizaki, M. (2004) Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species. Cancer Res, 64, 1071-1078. 8. Kang, H.J., Soh, Y., Kim, M.S., Lee, E.J., Surh, Y.J., Kim, H.R., Kim, S.H. and Moon, A. (2003) Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras-transformed human breast epithelial cells. Int J Cancer, 103, 475-482. 9. Kerr, J.F., Wyllie, A.H. and Currie, A.R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer, 26, 239-257. 10. Kim, S. and Moon, A. (2004) Capsaicin-induced apoptosis of H-ras-transformed human breast epithelial cells is Rac-dependent via ROS generation. Arch Pharm Res, 27, 845-849. 11. LeBlanc, H.N. and Ashkenazi, A. (2003) Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ, 10, 66-75. 12. Lee, M.J., Kee, K.H., Suh, C.H., Lim, S.C. and Oh, S.H. (2009) Capsaicin-induced apoptosis is regulated by endoplasmic reticulum stress- and calpain-mediated mitochondrial cell death pathways. Toxicology, 264, 205-214. 13. Liu, S.C., Yang, J.J., Shao, K.N. and Chueh, P.J. (2008) RNA interference targeting tNOX attenuates cell migration via a mechanism that involves membrane association of Rac. Biochem Biophys Res Commun, 365, 672-677. 14. Mao, L.C., Wang, H.M., Lin, Y.Y., Chang, T.K., Hsin, Y.H. and Chueh, P.J. (2008) Stress-induced down-regulation of tumor-associated NADH oxidase during apoptosis in transformed cells. FEBS Lett, 582, 3445-3450. 15. Morre, D.J., Bridge, A., Wu, L.Y. and Morre, D.M. (2000) Preferential inhibition by (-)-epigallocatechin-3-gallate of the cell surface NADH oxidase and growth of transformed cells in culture. Biochem Pharmacol, 60, 937-946. 16. Morre, D.J., Chueh, P.J. and Morre, D.M. (1995) Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proc Natl Acad Sci U S A, 92, 1831-1835. 17. Morre, D.J., Kim, C., Paulik, M., Morre, D.M. and Faulk, W.P. (1997) Is the drug-responsive NADH oxidase of the cancer cell plasma membrane a molecular target for adriamycin? J Bioenerg Biomembr, 29, 269-280. 18. Morre, D.J., Sun, E., Geilen, C., Wu, L.Y., de Cabo, R., Krasagakis, K., Orfanos, C.E. and Morre, D.M. (1996) Capsaicin inhibits plasma membrane NADH oxidase and growth of human and mouse melanoma lines. Eur J Cancer, 32A, 1995-2003. 19. Nelson, E.K., and Dawson, L.E. (1923) The constitution of capsaicin, the pungent principle of capsicum. J. Am. Chem. Soc., 45, 2179-2181. 20. Szallasi, A. and Blumberg, P.M. (1999) Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev, 51, 159-212. 21. Szallasi, A., Cruz, F. and Geppetti, P. (2006) TRPV1: a therapeutic target for novel analgesic drugs? Trends Mol Med, 12, 545-554. 22. Taylor, R.C., Cullen, S.P. and Martin, S.J. (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol, 9, 231-241. 23. Thresh JC. (1876) Capsaicin, the active principle of capsicum fruits. Pharmaceut. Journal, 7, 21. 24. Wang, X. (2001) The expanding role of mitochondria in apoptosis. Genes Dev, 15, 2922-2933. 25. Wajant, H. (2002) The Fas signaling pathway: more than a paradigm. Science, 296, 1635-1636. 26. Wu, C.C., Lin, J.P., Yang, J.S., Chou, S.T., Chen, S.C., Lin, Y.T., Lin, H.L. and Chung, J.G. (2006) Capsaicin induced cell cycle arrest and apoptosis in human esophagus epidermoid carcinoma CE 81T/VGH cells through the elevation of intracellular reactive oxygen species and Ca2+ productions and caspase-3 activation. Mutat Res, 601, 71-82. 27. Yagiz, K., Morre, D.J. and Morre, D.M. (2006) Transgenic mouse line overexpressing the cancer-specific tNOX protein has an enhanced growth and acquired drug-response phenotype. J Nutr Biochem, 17, 750-759. 28. Zhang, R., Humphreys, I., Sahu, R.P., Shi, Y. and Srivastava, S.K. (2008) In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. Apoptosis, 13, 1465-1478.||摘要:||
Tumor-associated NADH oxidase (tNOX) 是一個存在於癌細胞膜上的蛋白，在過去的研究發現 tNOX 的活性及蛋白表現和癌細胞的生長息息相關，過度表現 tNOX 會導致非癌化細胞的轉型而使細胞具有侵犯性，而以 RNA干擾技術（RNAi）抑制 tNOX 表現，則會減弱 HeLa 細胞的生長與移動能力。除此之外，一些抑癌藥物 capsaicin、EGCG 等被發現會抑制tNOX 的活性與表現，同時也導致癌細胞的生長抑制與細胞凋亡，但 tNOX 與這些藥物造成的生長抑制之間的相關性卻並不清楚，因此在本篇研究之中，利用胃癌細胞株做為實驗模式，我們探討 capsaicin 所引發的生長抑制現象與tNOX 間的關聯性，
實驗的結果證實 capsaicin 的處理可在 SNU-1 與 TMC-1 之中引發生長抑制的現象。探討抑制的起因發現capsaicin 會導致 SNU-1 與 TMC-1 的細胞週期停滯在 G0/G1， 並調控其相關的基因表現。此外，capsaicin 的處理會在 SNU-1 造成活性氧分子（ROS）的增加、粒線體膜電位（MMP）的下降並引發細胞凋亡，但卻不影響另一胃癌細胞株 TMC-1。
為了釐清 TMC-1 細胞抗capsaicin 的原因，基於先前研究所推論的 capsaicin 與 tNOX 之間的相關性，我們進一步去分析 capsaicin 處理與 tNOX 表現之間的關聯。實驗結果證實在 TMC-1 之中 tNOX 的蛋白與 mRNA 表現是不受 capsaicin 所抑制，因此我們推測 tNOX對於 TMC-1 抗 capsaicin 能力中扮演一個重要的角色。透過 shRNA 抑制 tNOX 的基因表現，我們發現 tNOX-knockdown 的結果會導致 TMC-1 細胞對 capsaicin 的處理變的較為敏感，Capsaicin 刺激 tNOX knock down TMC-1 細胞會有更明顯的生長抑制現象，甚至造成ROS 的增加、MMP的下降，進而引發 細胞凋亡。由這些實驗證實，癌細胞中tNOX 的表現對於避免 capsaicin 所造成的細胞凋亡具有相當重要性。
Previous studies had revealed that activity and protein expression of tumor-associated NADH oxidase (tNOX) were closely related to growth of cancer cells. Overexpression tNOX induced transformation in non-cancer cells and knock down tNOX by RNA interference (RNAi) reduced cell growth and migration in HeLa cells. In addition, anti-tumor drugs such as capsaicin, EGCG were found to not only inhibit tNOX activity and protein level but also lead to growth inhibition and apoptosis in cancer cells. However, the correlation between growth inhibition by these drugs and tNOX is not clear. In this project, we studied the correlation between capsaicin-induced growth inhibition and tNOX protein in gastric cancer cell lines.
Our results showed that capsaicin treatment induced growth inhibition as well as cell cycle arrest in G0/G1 phase in SNU-1 and TMC-1. We also showed that capsaicin mediated generation of reactive oxygen species (ROS), reduction of mitochondrial membrane potential (MMP), and apoptotic signaling in SNU-1 but not in TMC-1. Base on previous studies demonstrating an association of cell growth and tNOX, we analyzed protein level of tNOX and established that capsaicin was unable to induce tNOX down-regulation in TMC-1. To confirm the role of tNOX in capsaicin-resistant TMC-1 cells, we supressed tNOX gene expression by shRNA and found that TMC-1 cells became more sensitive to capsaicin treatment. In tNOX knock down TMC-1 cells, capsaicin treatment induced greater growth inhibition, as well as generation of ROS, changes in MMP, and apoptosis. Our results suggested that the expression of tNOX in cancer cells was importance for capsaicin-mediated apoptosis.
|Appears in Collections:||生物醫學研究所|
Show full item record
TAIR Related Article
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.