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Research article

Bioactive Compounds and Chemical Biology

Anti-Metastasis Effects of Ginsenoside Rg3 in B16F10 Cells

Seul Gi Lee 1, Young Jin Kang 2 and Ju-Ock Nam 1*

1Department of Food Engineering, Kyungpook National University, Daegu 702-701, Republic of Korea, 2Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 702-701, Republic of Korea

Received: June 2, 2015; Accepted: September 11, 2015

J. Microbiol. Biotechnol. 2015; 25(12): 1997-2006

Published December 28, 2015 https://doi.org/10.4014/jmb.1506.06002

Copyright © The Korean Society for Microbiology and Biotechnology.

Abstract

Ginsenoside Rg3 is a bioactive ginseng constituent that has been reported to have diverse pathological and physiological effects, including anti-inflammatory and anti-metastatic activities. Metastasis is one of the most important factors involved in patients with melanoma. However, the molecular mechanism underlying the anti-metastatic activities of Rg3 in malignant melanoma cancer has not been fully elucidated. In this study, we have evaluated that Rg3 effectively inhibits metastasis of B16F10 melanoma cancer cells. We found that Rg3 significantly suppresses the migration, invasion, wound healing, and colony-forming abilities of B16F10 cells in a dose-dependent manner. Mechanistically, we demonstrate that Rg3 suppresses B16F10 cell metastasis by inhibiting MMP-13 expression. These results indicate that Rg3 suppresses the metastasis of B16F10 mouse melanoma cancer cells via MMP-13 regulation. Importantly, MMP-13 downregulation may influence the migration and invasion capabilities of melanoma cells and has been correlated with melanoma progression. Therefore, Rg3 is a potential therapeutic candidate that could be used to treat patients with metastatic melanoma.

Keywords

Ginsenoside, B16F10, metastasis, MMP13, cancer, migration

References

  1. Boregowda RK, Olabisi OO, Abushahba W, Jeong BS, Haenssen KK, Chen W, et al. 2014. RUNX2 is overexpressed in melanoma cells and mediates their migration and invasion. Cancer Lett. 348: 61-70.
    Pubmed PMC CrossRef
  2. Chalkiadaki G, Nikitovic D, Berdiaki A, Katonis P, Karamanos NK, Tzanakakis GN. 2 011. Hep arin p lays a k ey regulatory role via a p53/FAK-dependent signaling in melanoma cell adhesion and migration. IUBMB Life 63: 109-119.
    Pubmed
  3. Chen D, Li Y, Dai X, Zhou X, Tian W, Zhou Y, et al. 2013. 1,25-Dihydroxyvitamin D3 activates MMP13 gene expression in chondrocytes through p38 MARK pathway. Int. J. Biol. Sci. 9: 649-655.
    Pubmed PMC CrossRef
  4. Chen Y, Zheng L, Liu J, Zhou Z, Cao X, Lv X, Chen F. 2014. Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways. Int. Immunopharmacol. 21: 447-455.
    Pubmed CrossRef
  5. Chiang HM, Chan SY, Chu Y, Wen KC. 2015. Fisetin ameliorated photodamage by suppressing the MAP kinase/MMP pathway and NF-kappaB pathways. J. Agric. Food Chem.
    CrossRef
  6. Jeong YJ, Choi Y, Shin JM, Cho HJ, Kang JH, Park KK, et al. 2014. Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K/Akt/mTOR signaling pathway in breast cancer cells. Food Chem. Toxicol. 68: 218-225.
    Pubmed CrossRef
  7. Jia D, Yan M, Wang X, Hao X, Liang L, Liu L, et al. 2010. Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion. BMC Cancer 10: 364.
    Pubmed PMC CrossRef
  8. Jimenez RE, Hartwig W, Antoniu BA, Compton CC, Warshaw AL, Fernandez-Del Castillo C. 2000. Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: an additive strategy for cancer control. Ann. Surg. 231: 644-654.
    Pubmed PMC CrossRef
  9. Kim JS, Joo EJ, Chun J, Ha YW, Lee JH, Han Y, Kim YS. 2012. Induction of apoptosis by ginsenoside Rk1 in SKMEL2-human melanoma. Arch. Pharm. Res. 35: 717-722.
    Pubmed CrossRef
  10. Kim JW, Jung SY, Kwon YH, Lee JH, Lee YM, Lee BY, Kwon SM. 2012. Ginsenoside Rg3 attenuates tumor angiogenesis via inhibiting bioactivities of endothelial progenitor cells. Cancer Biol. Ther. 13: 504-515.
    Pubmed CrossRef
  11. Kim SM, Lee SY, Cho JS, Son SM, Choi SS, Yun YP, et al. 2010. Combination of ginsenoside Rg3 with docetaxel enhances the susceptibility of prostate cancer cells via inhibition of NF-kappaB. Eur. J. Pharmacol. 631: 1-9.
    Pubmed CrossRef
  12. Kim YJ, Choi WI, Jeon BN, Choi KC, Kim K, Kim TJ, et al. 2014. Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-beta1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance. Toxicology 322: 23-33.
    Pubmed CrossRef
  13. Ko SY, Ko HA, Shieh TM, Chang WC, Chen HI, Chang SS, Lin IH. 2014. Cell migration is regulated by AGE-RAGE interaction in human oral cancer cells in vitro. PLoS One 9:e110542.
    Pubmed PMC CrossRef
  14. Lecomte J, Masset A, Blacher S, Maertens L, Gothot A, Delgaudine M, et al. 2012. Bone marrow-derived myofibroblasts are the providers of pro-invasive matrix metalloproteinase 13 in primary tumor. Neoplasia 14: 943-951.
    Pubmed PMC CrossRef
  15. Lee SG, Kim BS, Nam J-O. 2014. Ginsenoside Rg3 induces apoptosis in B16F10 melanoma cells. Kor. J. Life Sci. 24:1001-1009.
    CrossRef
  16. Meierjohann S, Hufnagel A, Wende E, Kleinschmidt MA, Wolf K, Friedl P, et al. 2010. MMP13 mediates cell cycle progression in melanocytes and melanoma cells: in vitro studies of migration and proliferation. Mol. Cancer 9: 201.
    Pubmed PMC CrossRef
  17. Ozawa H, Sonoda Y, Kato S, Suzuki E, Matsuoka R, Kanaya T, et al. 2012. Sulfatides inhibit adhesion, migration, and invasion of murine melanoma B16F10 cell line in vitro. Biol. Pharm. Bull. 35: 2054-2058.
    Pubmed CrossRef
  18. Pivetta E, Scapolan M, Pecolo M, Wassermann B, AbuRumeileh I, Balestreri L, et al. 2011. MMP-13 stimulates osteoclast differentiation and activation in tumour breast bone metastases. Breast Cancer Res. 13: R105.
    Pubmed PMC CrossRef
  19. Song Y, Park HJ, Kang SN, Jang SH, Lee SJ, Ko YG, et al. 2013. Blueberry peel extracts inhibit adipogenesis in 3T3-L1 cells and reduce high-fat diet-induced obesity. PLoS One 8:e69925.
    Pubmed PMC CrossRef
  20. Tsai HE, Wu JC, Kung ML, Liu LF, Kuo LH, Kuo HM, et al. 2013. Up-regulation of hepatoma-derived growth factor facilitates tumor progression in malignant melanoma [corrected]. PLoS One 8: e59345.
    Pubmed PMC CrossRef
  21. Wang Z, Jiang C, Chen W. 2014. Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells. 2014: 732516.
  22. Westermarck J, Kahari VM. 1999. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 13: 781-792.
    Pubmed
  23. Xu TM, Cui MH, Xin Y, Gu LP, Jiang X, Su MM, et al. 2008. Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis. Chin. Med. J. (Engl.) 121: 1394-1397.
  24. Yamada T, Oshima T, Yoshihara K, Tamura S, Kanazawa A, Inagaki D, et al. 2010. Overexpression of MMP-13 gene in colorectal cancer with liver metastasis. Anticancer Res. 30:2693-2699.
    Pubmed
  25. Yong HY, Koh MS, Moon A. 2009. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Exp. Opin. Invest. Drugs 18: 1893-1905.
    Pubmed CrossRef
  26. Zehavi L, Schayek H, Jacob-Hirsch J, Sidi Y, Leibowitz-Amit R, Avni D. 2015. MiR-377 targets E2F3 and alters the NF-kB signaling pathway through MAP3K7 in malignant melanoma. Mol. Cancer 14: 68.
    Pubmed PMC CrossRef
  27. Zhang P, Huang C, Fu C, Tian Y, Hu Y, Wang B, et al. 2015. Cordycepin (3'-deoxyadenosine) suppressed HMGA2, Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b. Oncotarget 6: 9834-9853.
    Pubmed PMC CrossRef
  28. Zhao X, Pang L, Qian Y, Wang Q, Li Y, Wu M, et al. 2013. An animal model of buccal mucosa cancer and cervical lymph node metastasis induced by U14 squamous cell carcinoma cells. Exp. Ther. Med. 5: 1083-1088.
    Pubmed PMC

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Article

Research article

J. Microbiol. Biotechnol. 2015; 25(12): 1997-2006

Published online December 28, 2015 https://doi.org/10.4014/jmb.1506.06002

Copyright © The Korean Society for Microbiology and Biotechnology.

Anti-Metastasis Effects of Ginsenoside Rg3 in B16F10 Cells

Seul Gi Lee 1, Young Jin Kang 2 and Ju-Ock Nam 1*

1Department of Food Engineering, Kyungpook National University, Daegu 702-701, Republic of Korea, 2Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 702-701, Republic of Korea

Received: June 2, 2015; Accepted: September 11, 2015

Abstract

Ginsenoside Rg3 is a bioactive ginseng constituent that has been reported to have diverse
pathological and physiological effects, including anti-inflammatory and anti-metastatic
activities. Metastasis is one of the most important factors involved in patients with melanoma.
However, the molecular mechanism underlying the anti-metastatic activities of Rg3 in
malignant melanoma cancer has not been fully elucidated. In this study, we have evaluated
that Rg3 effectively inhibits metastasis of B16F10 melanoma cancer cells. We found that Rg3
significantly suppresses the migration, invasion, wound healing, and colony-forming abilities
of B16F10 cells in a dose-dependent manner. Mechanistically, we demonstrate that Rg3
suppresses B16F10 cell metastasis by inhibiting MMP-13 expression. These results indicate
that Rg3 suppresses the metastasis of B16F10 mouse melanoma cancer cells via MMP-13
regulation. Importantly, MMP-13 downregulation may influence the migration and invasion
capabilities of melanoma cells and has been correlated with melanoma progression. Therefore,
Rg3 is a potential therapeutic candidate that could be used to treat patients with metastatic
melanoma.

Keywords: Ginsenoside, B16F10, metastasis, MMP13, cancer, migration

References

  1. Boregowda RK, Olabisi OO, Abushahba W, Jeong BS, Haenssen KK, Chen W, et al. 2014. RUNX2 is overexpressed in melanoma cells and mediates their migration and invasion. Cancer Lett. 348: 61-70.
    Pubmed KoreaMed CrossRef
  2. Chalkiadaki G, Nikitovic D, Berdiaki A, Katonis P, Karamanos NK, Tzanakakis GN. 2 011. Hep arin p lays a k ey regulatory role via a p53/FAK-dependent signaling in melanoma cell adhesion and migration. IUBMB Life 63: 109-119.
    Pubmed
  3. Chen D, Li Y, Dai X, Zhou X, Tian W, Zhou Y, et al. 2013. 1,25-Dihydroxyvitamin D3 activates MMP13 gene expression in chondrocytes through p38 MARK pathway. Int. J. Biol. Sci. 9: 649-655.
    Pubmed KoreaMed CrossRef
  4. Chen Y, Zheng L, Liu J, Zhou Z, Cao X, Lv X, Chen F. 2014. Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways. Int. Immunopharmacol. 21: 447-455.
    Pubmed CrossRef
  5. Chiang HM, Chan SY, Chu Y, Wen KC. 2015. Fisetin ameliorated photodamage by suppressing the MAP kinase/MMP pathway and NF-kappaB pathways. J. Agric. Food Chem.
    CrossRef
  6. Jeong YJ, Choi Y, Shin JM, Cho HJ, Kang JH, Park KK, et al. 2014. Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K/Akt/mTOR signaling pathway in breast cancer cells. Food Chem. Toxicol. 68: 218-225.
    Pubmed CrossRef
  7. Jia D, Yan M, Wang X, Hao X, Liang L, Liu L, et al. 2010. Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion. BMC Cancer 10: 364.
    Pubmed KoreaMed CrossRef
  8. Jimenez RE, Hartwig W, Antoniu BA, Compton CC, Warshaw AL, Fernandez-Del Castillo C. 2000. Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: an additive strategy for cancer control. Ann. Surg. 231: 644-654.
    Pubmed KoreaMed CrossRef
  9. Kim JS, Joo EJ, Chun J, Ha YW, Lee JH, Han Y, Kim YS. 2012. Induction of apoptosis by ginsenoside Rk1 in SKMEL2-human melanoma. Arch. Pharm. Res. 35: 717-722.
    Pubmed CrossRef
  10. Kim JW, Jung SY, Kwon YH, Lee JH, Lee YM, Lee BY, Kwon SM. 2012. Ginsenoside Rg3 attenuates tumor angiogenesis via inhibiting bioactivities of endothelial progenitor cells. Cancer Biol. Ther. 13: 504-515.
    Pubmed CrossRef
  11. Kim SM, Lee SY, Cho JS, Son SM, Choi SS, Yun YP, et al. 2010. Combination of ginsenoside Rg3 with docetaxel enhances the susceptibility of prostate cancer cells via inhibition of NF-kappaB. Eur. J. Pharmacol. 631: 1-9.
    Pubmed CrossRef
  12. Kim YJ, Choi WI, Jeon BN, Choi KC, Kim K, Kim TJ, et al. 2014. Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-beta1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance. Toxicology 322: 23-33.
    Pubmed CrossRef
  13. Ko SY, Ko HA, Shieh TM, Chang WC, Chen HI, Chang SS, Lin IH. 2014. Cell migration is regulated by AGE-RAGE interaction in human oral cancer cells in vitro. PLoS One 9:e110542.
    Pubmed KoreaMed CrossRef
  14. Lecomte J, Masset A, Blacher S, Maertens L, Gothot A, Delgaudine M, et al. 2012. Bone marrow-derived myofibroblasts are the providers of pro-invasive matrix metalloproteinase 13 in primary tumor. Neoplasia 14: 943-951.
    Pubmed KoreaMed CrossRef
  15. Lee SG, Kim BS, Nam J-O. 2014. Ginsenoside Rg3 induces apoptosis in B16F10 melanoma cells. Kor. J. Life Sci. 24:1001-1009.
    CrossRef
  16. Meierjohann S, Hufnagel A, Wende E, Kleinschmidt MA, Wolf K, Friedl P, et al. 2010. MMP13 mediates cell cycle progression in melanocytes and melanoma cells: in vitro studies of migration and proliferation. Mol. Cancer 9: 201.
    Pubmed KoreaMed CrossRef
  17. Ozawa H, Sonoda Y, Kato S, Suzuki E, Matsuoka R, Kanaya T, et al. 2012. Sulfatides inhibit adhesion, migration, and invasion of murine melanoma B16F10 cell line in vitro. Biol. Pharm. Bull. 35: 2054-2058.
    Pubmed CrossRef
  18. Pivetta E, Scapolan M, Pecolo M, Wassermann B, AbuRumeileh I, Balestreri L, et al. 2011. MMP-13 stimulates osteoclast differentiation and activation in tumour breast bone metastases. Breast Cancer Res. 13: R105.
    Pubmed KoreaMed CrossRef
  19. Song Y, Park HJ, Kang SN, Jang SH, Lee SJ, Ko YG, et al. 2013. Blueberry peel extracts inhibit adipogenesis in 3T3-L1 cells and reduce high-fat diet-induced obesity. PLoS One 8:e69925.
    Pubmed KoreaMed CrossRef
  20. Tsai HE, Wu JC, Kung ML, Liu LF, Kuo LH, Kuo HM, et al. 2013. Up-regulation of hepatoma-derived growth factor facilitates tumor progression in malignant melanoma [corrected]. PLoS One 8: e59345.
    Pubmed KoreaMed CrossRef
  21. Wang Z, Jiang C, Chen W. 2014. Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells. 2014: 732516.
  22. Westermarck J, Kahari VM. 1999. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 13: 781-792.
    Pubmed
  23. Xu TM, Cui MH, Xin Y, Gu LP, Jiang X, Su MM, et al. 2008. Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis. Chin. Med. J. (Engl.) 121: 1394-1397.
  24. Yamada T, Oshima T, Yoshihara K, Tamura S, Kanazawa A, Inagaki D, et al. 2010. Overexpression of MMP-13 gene in colorectal cancer with liver metastasis. Anticancer Res. 30:2693-2699.
    Pubmed
  25. Yong HY, Koh MS, Moon A. 2009. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Exp. Opin. Invest. Drugs 18: 1893-1905.
    Pubmed CrossRef
  26. Zehavi L, Schayek H, Jacob-Hirsch J, Sidi Y, Leibowitz-Amit R, Avni D. 2015. MiR-377 targets E2F3 and alters the NF-kB signaling pathway through MAP3K7 in malignant melanoma. Mol. Cancer 14: 68.
    Pubmed KoreaMed CrossRef
  27. Zhang P, Huang C, Fu C, Tian Y, Hu Y, Wang B, et al. 2015. Cordycepin (3'-deoxyadenosine) suppressed HMGA2, Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b. Oncotarget 6: 9834-9853.
    Pubmed KoreaMed CrossRef
  28. Zhao X, Pang L, Qian Y, Wang Q, Li Y, Wu M, et al. 2013. An animal model of buccal mucosa cancer and cervical lymph node metastasis induced by U14 squamous cell carcinoma cells. Exp. Ther. Med. 5: 1083-1088.
    Pubmed KoreaMed