Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Gomisin G Inhibits the Growth of Triple-Negative Breast Cancer Cells by Suppressing AKT Phosphorylation and Decreasing Cyclin D1

  • Maharjan, Sony (Center for Medical Science Research, College of Medicine, Hallym University) ;
  • Park, Byoung Kwon (Center for Medical Science Research, College of Medicine, Hallym University) ;
  • Lee, Su In (Center for Medical Science Research, College of Medicine, Hallym University) ;
  • Lim, Yoonho (Division of Bioscience and Biotechnology, BMIC, Konkuk University) ;
  • Lee, Keunwook (Department of Biomedical Science, College of Natural Science, Hallym University) ;
  • Kwon, Hyung-Joo (Center for Medical Science Research, College of Medicine, Hallym University)
  • Received : 2017.11.30
  • Accepted : 2018.01.09
  • Published : 2018.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

A type of breast cancer with a defect in three molecular markers such as the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor is called triple-negative breast cancer (TNBC). Many patients with TNBC have a lower survival rate than patients with other types due to a poor prognosis. In this study, we confirmed the anti-cancer effect of a natural compound, Gomisin G, in TNBC cancer cells. Treatment with Gomisin G suppressed the viability of two TNBC cell lines, MDA-MB-231 and MDA-MB-468 but not non-TNBC cell lines such as MCF-7, T47D, and ZR75-1. To investigate the molecular mechanism of this activity, we examined the signal transduction pathways after treatment with Gomisin G in MDA-MB-231 cells. Gomisin G did not induce apoptosis but drastically inhibited AKT phosphorylation and reduced the amount of retinoblastoma tumor suppressor protein (Rb) and phosphorylated Rb. Gomisin G induced in a proteasome-dependent manner a decrease in Cyclin D1. Consequently, Gomisin G causes cell cycle arrest in the G1 phase. In contrast, there was no significant change in T47D cells except for a mild decrease in AKT phosphorylation. These results show that Gomisin G has an anti-cancer activity by suppressing proliferation rather than inducing apoptosis in TNBC cells. Our study suggests that Gomisin G could be used as a therapeutic agent in the treatment of TNBC patients.

Keywords

References

  1. Alao, J. P. (2007) The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Mol. Cancer 6, 24.
  2. Altomare, D. A. and Testa, J. R. (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24, 7455-7464. https://doi.org/10.1038/sj.onc.1209085
  3. Anders, C. K. and Carey, L. A. (2009) Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin. Breast Cancer 9 Suppl 2, S73-S81. https://doi.org/10.3816/CBC.2009.s.008
  4. Arcaro, A. and Guerreiro, A. S. (2007) The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr. Genomics 8, 271-306. https://doi.org/10.2174/138920207782446160
  5. Bartkova, J., Lukas, J., Muller, H., Lutzhoft, D., Strauss, M. and Bartek, J. (1994) Cyclin D1 protein expression and function in human breast cancer. Int. J. Cancer 57, 353-361. https://doi.org/10.1002/ijc.2910570311
  6. Caputi, M., Groeger, A. M., Esposito, V., Dean, C., De Luca, A., Pacilio, C., Muller, M. R., Giordano, G. G., Baldi, F., Wolner, E. and Giordano, A. (1999) Prognostic role of cyclin D1 in lung cancer. Relationship to proliferating cell nuclear antigen. Am. J. Respir. Cell. Mol. Biol. 20, 746-750. https://doi.org/10.1165/ajrcmb.20.4.3366
  7. Casimiro, M. C., Crosariol, M., Loro, E., Li, Z. and Pestell, R. G. (2012) Cyclins and cell cycle control in cancer and disease. Genes Cancer 3, 649-657. https://doi.org/10.1177/1947601913479022
  8. Chang, F., Lee, J. T., Navolanic, P. M., Steelman, L. S., Shelton, J. G., Blalock, W. L., Franklin, R. A. and McCubrey, J. A. (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17, 590-603. https://doi.org/10.1038/sj.leu.2402824
  9. Chavez, K. J., Garimella, S. V. and Lipkowitz, S. (2010) Triple negative breast cancer cell lines: one tool in the search for better treatment of triple negative breast cancer. Breast Dis. 32, 35-48.
  10. Chen, D. F., Zhang, S. X., Xie, L., Xie, J. X., Chen, K., Kashiwada, Y., Zhou, B. N., Wang, P., Cosentino, L. M. and Lee, K. H. (1997) Anti-AIDS agents--XXVI. Structure-activity correlations of gomisin- G-related anti-HIV lignans from Kadsura interior and of related synthetic analogues. Bioorg. Med. Chem. 5, 1715-1723. https://doi.org/10.1016/S0968-0896(97)00118-1
  11. Choi, Y. W., Takamatsu, S., Khan, S. I., Srinivas, P. V., Ferreira, D., Zhao, J. and Khan, I. A. (2006) Schisandrene, a dibenzocyclooctadiene lignan from Schisandra chinensis: structure-antioxidant activity relationships of dibenzocyclooctadiene lignans. J. Nat. Prod. 69, 356-359. https://doi.org/10.1021/np0503707
  12. Collignon, J., Lousberg, L., Schroeder, H. and Jerusalem, G. (2016) Triple-negative breast cancer: treatment challenges and solutions. Breast Cancer (Dove Med. Press) 8, 93-107.
  13. Criscitiello, C., Azim, H. A., Jr., Schouten, P. C., Linn, S. C. and Sotiriou, C. (2012) Understanding the biology of triple-negative breast cancer. Ann. Oncol. 23 Suppl 6, vi13-vi18. https://doi.org/10.1093/annonc/mds438
  14. Dent, R., Trudeau, M., Pritchard, K. I., Hanna, W. M., Kahn, H. K., Sawka, C. A., Lickley, L. A., Rawlinson, E., Sun, P. and Narod, S. A. (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin. Cancer Res. 13, 4429-4434. https://doi.org/10.1158/1078-0432.CCR-06-3045
  15. Fitzmaurice, C., Allen, C., Barber, R. M., Barregard, L., Bhutta, Z. A., Brenner, H. et al. (2017) Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 3, 524-548. https://doi.org/10.1001/jamaoncol.2016.5688
  16. Foulkes, W. D., Smith, I. E. and Reis-Filho, J. S. (2010) Triple-negative breast cancer. N. Engl. J. Med. 363, 1938-1948. https://doi.org/10.1056/NEJMra1001389
  17. Hutchinson, L. (2010) Breast cancer: challenges, controversies, breakthroughs. Nat. Rev. Clin. Oncol. 7, 669-670. https://doi.org/10.1038/nrclinonc.2010.192
  18. Jang, M. K., Yun, Y. R., Kim, J. H., Park, M. H. and Jung, M. H. (2017) Gomisin N inhibits adipogenesis and prevents high-fat diet-induced obesity. Sci. Rep. 7, 40345. https://doi.org/10.1038/srep40345
  19. Kang, J. I., Hong, J. Y., Choi, J. S. and Lee, S. K. (2016) Columbianadin inhibits cell proliferation by inducing apoptosis and necroptosis in HCT116 colon cancer cells. Biomol. Ther. (Seoul) 24, 320-327. https://doi.org/10.4062/biomolther.2015.145
  20. Kim, E. J., Kang, J. I., Tung, N. H., Kim, Y. H., Hyun, J. W., Koh, Y. S., Chang, W. Y., Yoo, E. S. and Kang, H. K. (2016) The effect of (1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-Olide (LS-1) from lobophyyum sp. on the apoptosis induction of SNU-C5 human colorectal cancer cells. Biomol. Ther. (Seoul) 24, 623-629. https://doi.org/10.4062/biomolther.2016.023
  21. Min, H. Y., Park, E. J., Hong, J. Y., Kang, Y. J., Kim, S. J., Chung, H. J., Woo, E. R., Hung, T. M., Youn, U. J., Kim, Y. S., Kang, S. S., Bae, K. and Lee, S. K. (2008) Antiproliferative effects of dibenzocyclooctadiene lignans isolated from Schisandra chinensis in human cancer cells. Bioorg. Med. Chem. Lett. 18, 523-526. https://doi.org/10.1016/j.bmcl.2007.11.082
  22. Musgrove, E. A., Caldon, C. E., Barraclough, J., Stone, A. and Sutherland, R. L. (2011) Cyclin D as a therapeutic target in cancer. Nat. Rev. Cancer 11, 558-572. https://doi.org/10.1038/nrc3090
  23. Oh, S. Y., Kim, Y. H., Bae, D. S., Um, B. H., Pan, C. H., Kim, C. Y., Lee, H. J. and Lee, J. K. (2010) Anti-inflammatory effects of gomisin N, gomisin J, and schisandrin C isolated from the fruit of Schisandra chinensis. Biosci. Biotechnol. Biochem. 74, 285-291. https://doi.org/10.1271/bbb.90597
  24. Opletal, L., Sovova, H. and Bartlova, M. (2004) Dibenzo[a,c]cyclooctadiene lignans of the genus Schisandra: importance, isolation and determination. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 812, 357-371. https://doi.org/10.1016/S1570-0232(04)00646-4
  25. Otto, T. and Sicinski, P. (2017) Cell cycle proteins as promising targets in cancer therapy. Nat. Rev. Cancer. 17, 93-115. https://doi.org/10.1038/nrc.2016.138
  26. Pareja, F., Geyer, F. C., Marchio, C., Burke, K. A., Weigelt, B. and Reis- Filho, J. S. (2016) Triple-negative breast cancer: the importance of molecular and histologic subtyping, and recognition of low-grade variants. NPJ Breast Cancer 2, 16036. https://doi.org/10.1038/npjbcancer.2016.36
  27. Park, H. J., Lee, S. J., Song, Y., Jang, S. H., Ko, Y. G., Kang, S. N., Chung, B. Y., Kim, H. D., Kim, G. S. and Cho, J. H. (2014) Schisandra chinensis prevents alcohol-induced fatty liver disease in rats. J. Med. Food 17, 103-110. https://doi.org/10.1089/jmf.2013.2849
  28. Qie, S. and Diehl, J. A. (2016) Cyclin D1, cancer progression, and opportunities in cancer treatment. J. Mol. Med. 94, 1313-1326. https://doi.org/10.1007/s00109-016-1475-3
  29. Robinson, T. J., Liu, J. C., Vizeacoumar, F., Sun, T., Maclean, N., Egan, S. E., Schimmer, A. D., Datti, A. and Zacksenhaus, E. (2013) RB1 status in triple negative breast cancer cells dictates response to radiation treatment and selective therapeutic drugs. PLoS ONE 8, e78641. https://doi.org/10.1371/journal.pone.0078641
  30. Ryu, E. Y., Park, S. Y., Kim, S. G., Park, D. J., Kang, J. S., Kim, Y. H., Seetharaman, R., Choi, Y. W. and Lee, S. J. (2011) Anti-inflammatory effect of heme oxygenase-1 toward Porphyromonas gingivalis lipopolysaccharide in macrophages exposed to gomisins A, G, and J. J. Med. Food 14, 1519-1526. https://doi.org/10.1089/jmf.2011.1656
  31. VanArsdale, T., Boshoff, C., Arndt, K. T. and Abraham, R. T. (2015) Molecular Pathways: Targeting the Cyclin D-CDK4/6 Axis for Cancer Treatment. Clin. Cancer Res. 21, 2905-2910. https://doi.org/10.1158/1078-0432.CCR-14-0816
  32. Xiaoyang, L., Chenming, N., Chengqing, L. and Tao, L. (2015) Drugdrug interation prediction between ketoconazole and anti-liver cancer drug Gomisin G. Afr. Health Sci. 15, 590-593. https://doi.org/10.4314/ahs.v15i2.35

Cited by

  1. A Novel Monoclonal Antibody Targets Mucin1 and Attenuates Growth in Pancreatic Cancer Model vol.19, pp.7, 2018, https://doi.org/10.3390/ijms19072004
  2. Potential of Schisandra chinensis (Turcz.) Baill. in Human Health and Nutrition: A Review of Current Knowledge and Therapeutic Perspectives vol.11, pp.2, 2019, https://doi.org/10.3390/nu11020333
  3. Gomisin G Suppresses the Growth of Colon Cancer Cells by Attenuation of AKT Phosphorylation and Arrest of Cell Cycle Progression vol.27, pp.2, 2018, https://doi.org/10.4062/biomolther.2018.054
  4. Generation and characterization of a monoclonal antibody against MERS-CoV targeting the spike protein using a synthetic peptide epitope-CpG-DNA-liposome complex vol.52, pp.6, 2019, https://doi.org/10.5483/bmbrep.2019.52.6.185
  5. Decursinol Angelate Ameliorates Dextran Sodium Sulfate-Induced Colitis by Modulating Type 17 Helper T Cell Responses vol.27, pp.5, 2019, https://doi.org/10.4062/biomolther.2019.004
  6. Probiotic Lactobacillus salivarius Ren prevent dimethylhydrazine-induced colorectal cancer through protein kinase B inhibition vol.104, pp.17, 2020, https://doi.org/10.1007/s00253-020-10775-w
  7. Decursinol Angelate Mitigates Sepsis Induced by Methicillin-Resistant Staphylococcus aureus Infection by Modulating the Inflammatory Responses of Macrophages vol.22, pp.20, 2018, https://doi.org/10.3390/ijms222010950
  8. Silencing of Pyruvate Kinase M2 via a Metal-Organic Framework Based Theranostic Gene Nanomedicine for Triple-Negative Breast Cancer Therapy vol.13, pp.48, 2021, https://doi.org/10.1021/acsami.1c18053