Abstract
2,6,6-Trimethylbicyclo[3.1.1]hept-2-ene (α-Pinene) is an organic compound of the terpene class found in the essential oil of many plants. In this study, the inhibitory effect of α-pinene on tumor invasion in highly metastatic MDA-MB-231 human breast cancer cells was evaluated. α-Pinene inhibited tumor necrosis factor (TNF)-α-induced invasiveness of MDA-MB-231 cells as revealed by three-dimensional spheroid invasion assay. Further analysis showed that α-pinene reduced TNFα-induced matrix metalloproteinase-9 gene promoter activation and mRNA expression in a dose-dependent manner. In addition, α-pinene treatment attenuated TNFα-induced nuclear factor κB (NF-κB) activation and NF-κB-dependent transcriptional activity. These results suggest that α-pinene has a significant effect on the inhibition of tumor invasion and may potentially be developed into an anti-metastatic drug.
This is a preview of subscription content, access via your institution.





References
Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev Cancer 9:361–371
Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125:5591–5596
Barnes PJ, Karin M (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:1066–1071
Chen W, Liu Y, Li M, Mao J, Zhang L, Huang R, Jin X, Ye L (2015) Anti-tumor effect of alpha-pinene on human hepatoma cell lines through inducing G2/M cell cycle arrest. J Pharmacol Sci 127:332–338
da Silva AC, Lopes PM, de Azevedo MM, Costa DC, Alviano CS, Alviano DS (2012) Biological activities of alpha-pinene and beta-pinene enantiomers. Molecules 17:6305–6316
Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25:9–34
Downes CP, Carter AN (1991) Phosphoinositide 3-kinase: a new effector in signal transduction? Cell Signal 3:501–513
Friedl P, Alexander S (2011) Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147:992–1009
Han YP, Tuan TL, Hughes M, Wu H, Garner WL (2001) Transforming growth factor-beta-and tumor necrosis factor-alpha-mediated induction and proteolytic activation of MMP-9 in human skin. J Biol Chem 276:22341–22350
Jing H, Zhou X, Dong X, Cao J, Zhu H, Lou J, Hu Y, He Q, Yang B (2010) Abrogation of Akt signaling by Isobavachalcone contributes to its anti-proliferative effects towards human cancer cells. Cancer Lett 294:167–177
Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252
Lee YH, Jeon SH, Kim SH, Kim C, Lee SJ, Koh D, Lim Y, Ha K, Shin SY (2012) A new synthetic chalcone derivative, 2-hydroxy-3′,5,5′-trimethoxychalcone (DK-139), suppresses the Toll-like receptor 4-mediated inflammatory response through inhibition of the Akt/NF-kappaB pathway in BV2 microglial cells. Exp Mol Med 44:369–377
Lee MS, Koh D, Kim GS, Lee SE, Noh HJ, Kim SY, Lee YH, Lim Y, Shin SY (2015) 2-Hydroxy-3,4-naphthochalcone (2H-NC) inhibits TNFalpha-induced tumor invasion through the downregulation of NF-kappaB-mediated MMP-9 gene expression. Bioorg Med Chem Lett 25:128–132
Lin CC, Tseng HW, Hsieh HL, Lee CW, Wu CY, Cheng CY, Yang CM (2008) Tumor necrosis factor-[alpha] induces MMP-9 expression via p42/p44 MAPK, JNK, and nuclear factor-[kappa]B in A549 cells. Toxicol Appl Pharmacol 229:386–398
Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin AS Jr, Mayo MW (2000) Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol Cell Biol 20:1626–1638
Madrid LV, Mayo MW, Reuther JY, Baldwin AS Jr (2001) Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 276:18934–18940
Mercier B, Prost J, Prost M (2009) The essential oil of turpentine and its major volatile fraction (alpha- and beta-pinenes): a review. Int J Occup Med Environ Health 22:331–342
Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85
Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466
Rao VH, Singh RK, Delimont DC, Finnell RH, Bridge JA, Neff JR, Garvin BP, Pickering DL, Sanger WG, Buehler BA, Schaefer GB (1999) Transcriptional regulation of MMP-9 expression in stromal cells of human giant cell tumor of bone by tumor necrosis factor-alpha. Int J Oncol 14:291–300
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101
Shin SY, Kim JH, Baker A, Lim Y, Lee YH (2010) Transcription factor Egr-1 is essential for maximal matrix metalloproteinase-9 transcription by tumor necrosis factor alpha. Mol Cancer Res 8:507–519
Shin SY, Kim JH, Yoon H, Choi YK, Koh D, Lim Y, Lee YH (2013a) Novel antimitotic activity of 2-hydroxy-4-methoxy-2′,3′-benzochalcone (HymnPro) through the inhibition of tubulin polymerization. J Agric Food Chem 61:12588–12597
Shin SY, Lee JM, Lim Y, Lee YH (2013b) Transcriptional regulation of the growth-regulated oncogene alpha gene by early growth response protein-1 in response to tumor necrosis factor alpha stimulation. Biochim Biophys Acta 1829:1066–1074
Ura H, Bonfil RD, Reich R, Reddel R, Pfeifer A, Harris CC, Klein-Szanto AJ (1989) Expression of type IV collagenase and procollagen genes and its correlation with the tumorigenic, invasive, and metastatic abilities of oncogene-transformed human bronchial epithelial cells. Cancer Res 49:4615–4621
Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G (2002) Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol 37:375–536
Acknowledgments
This study was supported by the Konkuk University research support program.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Kang, E., Lee, D.H., Jung, Y.J. et al. α-Pinene inhibits tumor invasion through downregulation of nuclear factor (NF)-κB-regulated matrix metalloproteinase-9 gene expression in MDA-MB-231 human breast cancer cells. Appl Biol Chem 59, 511–516 (2016). https://doi.org/10.1007/s13765-016-0175-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13765-016-0175-6
Keywords
- 2,6,6-Trimethylbicyclo[3.1.1]hept-2-ene
- Breast cancer
- Matrix metalloproteinase-9
- Nuclear factor kappa B
- Tumor invasion
- Tumor necrosis factor alpha