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α-Tomatine Suppresses Invasion and Migration of Human Non-Small Cell Lung Cancer NCI-H460 Cells Through Inactivating FAK/PI3K/Akt Signaling Pathway and Reducing Binding Activity of NF-κB

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Abstract

α-Tomatine, isolated from Lycopersicon esculentum Linn., is a naturally occurring steroidal glycoalkaloid in immature green tomatoes. Some reports demonstrated that α-tomatine had various anticarcinogenic properties. The purpose of this study is to investigate the anti-metastatic effect of α-tomatine in NCI-H460 human non-small cell lung cancer cells. First, the results showed that α-tomatine significantly suppressed the abilities of the adhesion, invasion, and migration of NCI-H460 cells under non-cytotoxic concentrations. Molecular data also showed α-tomatine could inhibit the activation of focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K)/Akt signal involve in the downregulation the enzyme activities, protein and messenger RNA levels of matrix metalloproteinase-7 (MMP-7). Next, α-tomatine also strongly inhibited the degradation of inhibitor of kappaBα (IκBα) and the nuclear levels of nuclear factor kappa B (NF-κB). Also, a dose-dependent inhibition on the binding ability of NF-κB by α-tomatine treatment was further observed. Furthermore, α-tomatine significantly decreased the levels of phospho-Akt and MMP-7 in Akt1-cDNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. Presented results indicated α-tomatine might be further application for treating cancer metastasis.

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Abbreviations

MMPs:

Matrix metalloproteinases

ECM:

Extracellular matrix

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signaling-regulating kinase

JNK/SAPK:

c-Jun N-terminal kinase/stress-activated protein kinase

PI3K:

Phosphoinositide 3-kinase

NF-κb:

Nuclear factor kappa B

AP-1:

Activator protein-1

IκB:

Inhibitor of NF-κB

References

  1. Greenlee, R. T., Hill-Harmon, M. B., Murraym, T., & Thunm, M. (2001). Cancer statistics, 2001. CA: A Cancer Journal for Clinicians, 51, 15–36.

    Article  CAS  Google Scholar 

  2. Gupta, G. P., & Massague, J. (2006). Cancer metastasis: Building a framework. Cell, 127, 679–695.

    Article  PubMed  CAS  Google Scholar 

  3. Jemal, A., Murray, T., Ward, E., Samuels, A., Tiwari, R. C., Ghafoor, A., et al. (2005). Cancer statistics, 2005. CA: A Cancer Journal for Clinicians, 55, 10–30.

    Article  Google Scholar 

  4. Mitra, S. K., & Schlaepfer, D. D. (2006). Integrin-regulated FAK-Src signaling in normal and cancer cells. Current Opinion in Cell Biology, 18, 516–523.

    Article  PubMed  CAS  Google Scholar 

  5. Stupack, D. (2007). The biology of integrins. Oncology, 21, 6–12.

    PubMed  Google Scholar 

  6. van Nimwegen, M. J., & van dewater, B. (2007). Focal adhesion kinase: A potential target in cancer therapy. Biochemical Pharmacology, 73, 597–609.

    Article  PubMed  Google Scholar 

  7. Filder, I. J. (2005). The organ microenvironment and cancer metastasis. Differentiation, 70, 498–505.

    Google Scholar 

  8. Shih, Y. W., Chen, P. S., Wu, C. H., Jeng, Y. F., & Wang, C. J. (2007). α-Chaconine-reduced metastasis involves a PI3K/Akt signaling pathway with downregulation of NF-κB in human lung adenocarcinoma A549 cells. Journal of Agriculture and Food Chemistry, 55, 11035–11043.

    Article  CAS  Google Scholar 

  9. Khwaja, A. (1999). Akt is more than just a Bad kinase. Nature, 401, 33–34.

    Article  PubMed  CAS  Google Scholar 

  10. Chan-Hui, P. Y., & Weaver, R. (1998). Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. The Biochemical Journal, 336, 599–609.

    PubMed  CAS  Google Scholar 

  11. Trusolino, L., & Comoglio, P. M. (2002). Scatter-factor and semaphoring receptors: Cell signalling for invasive growth. Nature Reviews Cancer, 2, 289–300.

    Article  PubMed  CAS  Google Scholar 

  12. Chen, P. N., Hsieh, Y. S., Chiou, H. L., & Chu, S. C. (2005). Silibinin inhibits cell invasion through inactivation of both PI3K-Akt and MAPK signaling pathways. Chemico-Biological Interactions, 156, 141–150.

    Article  PubMed  CAS  Google Scholar 

  13. Kwon, G. T., Cho, H. J., Chung, W. Y., Park, K. K., Moon, A., & Park, J. H. (2009). Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: possible mediation by decreased JNK/AP-1 signaling. The Journal of Nutritional Biochemistry, 20, 663–676.

    Article  PubMed  CAS  Google Scholar 

  14. Lee, S. J., Park, S. S., Lee, U. S., Kim, W. J., & Moon, S. K. (2008). Signaling pathway for TNF-alpha-induced MMP-9 expression: Mediation through p38 MAP kinase, and inhibition by anti-cancer molecule magnolol in human urinary bladder cancer 5637 cells. International Immunopharmacology, 8, 1821–1826.

    Article  PubMed  CAS  Google Scholar 

  15. Nagase, H., & Woessner, J. F., Jr. (1999). Matrix metalloproteinases. The Journal of Biological Chemistry, 274, 21491–21494.

    Article  PubMed  CAS  Google Scholar 

  16. Westermarck, J., & Kahari, V. M. (1999). Regulation of matrix metalloproteinase expression in tumor invasion. The FASEB Journal, 13, 781–792.

    PubMed  CAS  Google Scholar 

  17. Viatour, P., Merville, M. P., Bours, V., & Chariot, A. (2005). Phosphorylation of NF-kappaB and IkappaB proteins: Implications in cancer and inflammation. Trends in Biochemical Sciences, 30, 43–52.

    Article  PubMed  CAS  Google Scholar 

  18. Karin, M., & Ben-Neriah, Y. (2000). Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity. Annual Review of Immunology, 18, 621–663.

    Article  PubMed  CAS  Google Scholar 

  19. Kunnumakkara, A. B., Anand, P., & Aggarwal, B. B. (2008). Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Letters, 269, 199–225.

    Article  PubMed  CAS  Google Scholar 

  20. Lee, S. O., Jeong, Y. J., Im, H. G., Kim, C. H., Chang, Y. C., & Lee, I. S. (2007). Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells. Biochemical and Biophysical Research Communications, 354, 165–171.

    Article  PubMed  CAS  Google Scholar 

  21. Friedman, M., & Levin, C. E. (1995). α-Tomatine content in tomato and tomato products determined by HPLC with pulsed amperometric detection. Journal of Agriculture and Food Chemistry, 43, 1507–1511.

    Article  CAS  Google Scholar 

  22. Lee, K. R., Kozukue, N., Han, J. S., Park, J. H., Chang, E. Y., Baek, E. J., et al. (2004). Glycoalkaloids and metabolites inhibit the growth of human colon (HT29) and liver (HepG2) cancer cells. Journal of Agriculture and Food Chemistry, 52, 2832–2839.

    Article  CAS  Google Scholar 

  23. Morrow, W. J. W., Yang, Y. W., & Sheikh, N. A. (2004). Immunobiology of the tomatine adjuvant. Vaccine, 2004(22), 2380–2384.

    Article  Google Scholar 

  24. Chiu, F. L., & Lin, J. K. (2008). Tomatidine inhibits iNOS and COX-2 through suppression of NF-κB and JNK pathways in LPS-stimulated mouse macrophages. FEBS Letters, 582, 2407–2412.

    Article  PubMed  CAS  Google Scholar 

  25. Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65, 55–63.

    Article  PubMed  CAS  Google Scholar 

  26. LeBel, C. P., Ischiopoulos, H., & Bondy, S. C. (1992). Evaluation of the probe 2,7-dichloro-fluorescin as indicator of reactive oxygen species formation and oxidative stress. Chemical Research in Toxicology, 5, 227–231.

    Article  PubMed  CAS  Google Scholar 

  27. Hisin, P. J., & Hilf, R. (1976). A fluorometric method for determination of oxidized and reduced glutathione in tissues. Analytical Biochemistry, 74, 214–226.

    Article  Google Scholar 

  28. Ochi, Y., Atsumi, S., Aoyagi, T., & Umezawa, K. (1993). Inhibition of tumor cell invasion in the Boyden chamber assay by a mannosidase inhibitor, mannostatin A. Anticancer Research, 13, 1421–1424.

    PubMed  CAS  Google Scholar 

  29. Chu, S. C., Chiou, H. L., Chen, P. N., Yang, S. F., & Hsieh, Y. S. (2004). Silibinin inhibits the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2. Molecular Carcinogenesis, 40, 143–149.

    Article  PubMed  CAS  Google Scholar 

  30. Ito, H., Duxbury, M., Benoit, E., Clancy, T. E., Zinner, M. J., Ashley, S. W., et al. (2004). Prostaglandin E2 enhances pancreatic cancer invasiveness through an Ets-1-dependent induction of matrix metalloproteinase-2. Cancer Research, 64, 7439–7446.

    Article  PubMed  CAS  Google Scholar 

  31. Ma, W., Lim, W., Gee, K., Aucoin, S., Nandan, D., Kozlowski, M., et al. (2001). The p38 mitogen-activated kinase pathway regulates the human interleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccharide stimulated human macrophages. The Journal of biological chemistry, 276, 13664–13674.

    PubMed  CAS  Google Scholar 

  32. Lin, H. H., Chen, J. H., Kuo, W. H., & Wang, C. J. (2007). Chemopreventive properties of Hibiscus sabdariffa L. on human gastric carcinoma cells through apoptosis induction and JNK/p38 MAPK signaling activation. Chemico-Biological Interactions, 165, 59–75.

    Article  PubMed  CAS  Google Scholar 

  33. Chandra, J., Samali, A., & Orrenius, S. (2000). Triggering and modulation of apoptosis by oxidative stress. Free Radical Biology and Medicine, 29, 323–333.

    Article  PubMed  CAS  Google Scholar 

  34. Chakraborti, S., Mandal, M., Das, S., Mandal, A., & Chakraborti, T. (2003). Regulation of matrix metalloproteinases: An overview. Molecular and Cellular Biochemistry, 253, 269–285.

    Article  PubMed  CAS  Google Scholar 

  35. Brockman, J. A., Scherer, D. C., McKinsey, T. A., Hall, S. M., Qi, X., Lee, W. Y., et al. (1995). Coupling of a signal response domain in IκBa to multiple pathways for NF-kB activation. Molecular and Cellular Biology, 15, 2809–2818.

    PubMed  CAS  Google Scholar 

  36. Chataing, B., Concepcion, J. L., de Cristancho, N. B., & Usubillaga, A. (1997). Estudio clinico de la efectividad de extractos alcaloides obtenidos de los frutos del Solanum americanum Miller sobre el Herpes simplex, Herpes Zoster y Herpes genitalis. Revista de la Facultad de Farmacia, 32, 18–25.

    Google Scholar 

  37. McGehee, D. S., Krasowski, M. D., Fung, D. L., Wilson, B., Gronert, G. A., & Moss, J. (2000). Cholinesterase inhibition by potato glycoalkaloids slows mivacurium metabolism. Anesthesiology, 93, 510–519.

    Article  PubMed  CAS  Google Scholar 

  38. Rajananthanan, P., Attard, G. S., Sheikhh, N., & Morrow, W. J. (2000). Novel aggregate structure modulate lymphocyte proliferation and Th1 and Th2 cytokine profiles in ovalbumin immunized mice. Vaccine, 18, 140–152.

    Article  Google Scholar 

  39. Parsons, J. T. (2003). Focal adhesion kinase: The first ten years. Journal of Cell Science, 116, 1409–1416.

    Article  PubMed  CAS  Google Scholar 

  40. Fujii, T., Koshikawa, K., Nomoto, S., Okochi, O., Kaneko, T., Inoue, S., et al. (2004). Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor. Journal of Hepatology, 41, 104–111.

    Article  PubMed  CAS  Google Scholar 

  41. Mukhopadhyay, N. K., Gordon, G. J., Chen, C. J., Bueno, R., Sugarbaker, D. J., & Jaklitsch, M. T. (2005). Activation of focal adhesion kinase in human lung cancer cells involves multiple and potentially parallel signaling events. Journal of Cellular and Molecular Medicine, 9, 387–397.

    Article  PubMed  CAS  Google Scholar 

  42. Akasaka, T., van Leeuwen, R. L., Yoshinaga, I. G., Mihm, M. C., & Byers, H. H. (1995). Focal adhesion kinase (p125FAK) expression correlates with motility of human melanoma cell lines. The Journal of Investigative Dermatology, 105, 104–108.

    Article  PubMed  CAS  Google Scholar 

  43. Owens, L. V., Xu, L., Craven, R. G., Dent, G. A., Weiner, T. M., Kornberg, L., et al. (1995). Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Research, 55, 2752–2755.

    PubMed  CAS  Google Scholar 

  44. Weiner, T. M., Liu, E. T., Craven, R. J., & Cance, W. G. (1993). Expression of focal adhesion kinase gene and invasive cancer. Lancet, 342, 1024–1025.

    Article  PubMed  CAS  Google Scholar 

  45. Sonoda, Y., Watanabe, S., Matsumoto, Y., Aizu-Yokota, E., & Kasahara, T. (1999). FAK is the upstream signal protein of the phosphatidylinositol 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. The Journal of Biological Chemistry, 274, 10566–10570.

    Article  PubMed  CAS  Google Scholar 

  46. Huang, C., Jacobson, K., & Schaller, M. D. (2004). MAP kinases and cell migration. Journal of Cell Science, 117, 4619–4628.

    Article  PubMed  CAS  Google Scholar 

  47. Rudolph-Owen, L. A., Chan, R., Muller, W. J., & Matrisian, L. M. (1998). The matrix metalloproteinase matrilysin influences early stage mammary tumorigenesis. Cancer Research, 58, 5500–5506.

    PubMed  CAS  Google Scholar 

  48. Sasaki, H., Yukiue, H., Moiriyama, S., Kobayashi, Y., Nakashima, Y., Kaji, M., et al. (2001). Clinical significance of matrix metalloproteinase-7 and Ets-1 gene expression in patients with lung cancer. Journal of Surgical Research, 101, 242–247.

    Article  PubMed  CAS  Google Scholar 

  49. Aguirre Ghiso, J. A., Alonso, D. F., Farias, E. F., Gomez, D. E., & de Kier Joffe, E. B. (1999). Deregulation of the signaling pathways controlling urokinase production. Its relationship with the invasive phenotype. European Journal of Biochemistry, 263, 295–304.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Chest Medicine, Department of Internal Medicine, Chi-Mei Medical Center, No. 901, Jhong-Hua Road, Yong-Kang, Tainan, 710, Taiwan

    Jiunn-Min Shieh & Shian-Chin Ko

  2. Department of Respiratory Care, Chang Jung Christian University, Chang Jung Christian University, No. 396, Sect. 1, Chang Jung Road, Kway Jen, Tainan, 711, Taiwan

    Jiunn-Min Shieh & Shian-Chin Ko

  3. Department of Biological Science and Technology and Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, No. 89, Wen-Hwa 1st Street, Jen-Te, Tainan, 717, Taiwan

    Tsan-Hwang Cheng & Yuan-Wei Shih

  4. Department of Medical Technology, Yongkang Veterans Hospital, No. 427, Fu-Xing Road, Yong-Kang, Tainan, 710, Taiwan

    Ming-Der Shi

  5. Department of Medical Laboratory and Biotechnology Science, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung, 807, Taiwan

    Ming-Der Shi

  6. Department of Occupational Safety and Hygiene, Tajen University, No. 20, Wei-Sin Road, Yan-Pu, Pingtung, 907, Taiwan

    Pei-Fen Wu

  7. Department of Surgery, Tainan Municipal Hospital, No. 670, Chongde Road, Tainan, 701, Taiwan

    Yi Chen

  8. Department of Health Care Administration, Chung Hwa University of Medical Technology, No. 89, Wen-Hwa 1st Street, Jen-Te, Tainan, 717, Taiwan

    Yi Chen

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  1. Jiunn-Min Shieh
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Correspondence to Yuan-Wei Shih.

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Shieh, JM., Cheng, TH., Shi, MD. et al. α-Tomatine Suppresses Invasion and Migration of Human Non-Small Cell Lung Cancer NCI-H460 Cells Through Inactivating FAK/PI3K/Akt Signaling Pathway and Reducing Binding Activity of NF-κB. Cell Biochem Biophys 60, 297–310 (2011). https://doi.org/10.1007/s12013-011-9152-1

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