DOI QR코드

DOI QR Code

인간 유방암 세포주 MCF-7에 대한 farrerol의 p38 MAPK 활성화와 세포사멸 유도를 통한 항암 효과

Anti-cancer effect of farrerol induced apoptosis through activating p38 MAPK in Human breast cancer MCF-7 cells

  • Chae, Jongbeom (Department of Food Science and Biotechnology, Kyungpook National University) ;
  • Lee, Seul Gi (Department of Food Science and Biotechnology, Kyungpook National University) ;
  • Nam, Ju-Ock (Department of Food Science and Biotechnology, Kyungpook National University)
  • 투고 : 2020.02.27
  • 심사 : 2020.05.18
  • 발행 : 2020.06.30

초록

Farrerol은 중국에서 거담제로 사용되어온 전통 한약제로 사용된 산진달래(만산홍, Rhododendron dauricum L.)에서 유래된 플라바논이다. Farrerol은 항산화, 항염증 및 항균 작용을 포함한 다양한 생리 활성이 보고되었다. 하지만 farrerol의 MCF-7에 대한 항암 작용은 아직 보고된 바가 없다. 본 연구에서 인간 유방암 MCF-7 세포에 대한 farrerol의 처리가 세포증식을 억제하고 apoptosis를 유도함을 입증하였다. MCF-7 세포에 ferrerol을 48시간 동안 처리했을 때, 이는 통계적으로 유의한 세포증식 효과를 나타냈으며 이의 IC50 값은 145.04±1.4 μM임을 확인하였다. 또한, farrerol이 세포사멸을 유도함을 TUNEL assay와 FACS를 이용한 Annexin V/PI 염색을 통해 검증하였다. 이러한 항암 효능의 작용기전으로써, farrerol의 처리가 BAX/Bcl-2 및 Caspase-3활성화와 PARP 분절화를 증가시켜 세포자살을 촉진한다는 것을 확인하였다. 결론적으로, 본 연구의 결과는 farrerol이 apopotosis 관련 단백질의 활성 및 발현조절을 통해 MCF-7 유방암세포에 대한 항암 효능을 갖는다는 것을 보여주고 있다.

Farrerol is a flavanone isolated from the traditional Chinese herb 'Man-shan-hong' (Rhododendron dauricum L.). Farrerol has been reported to have various bioactivities including anti-oxidant, anti-inflammation, and anti-fungal. However, anti-cancer effect of farrerol has not yet been reported in MCF-7 breast cancer cells. In the present study, we investigated the anti-cancer effect of farrerol on MCF-7 cells. Farrerol decreased viability and induced apoptosis of MCF-7 cells in a dose dependent manner. Ferrerol exhibited a significant anti-proliferation effect with a half-maximal inhibitory concentration (IC50) values of 145.04±1.4 μM in MTT assay, when MCF-7 cells were treated with ferrerol for 48 h. Also, ferrerol induced apoptotic bodies of MCF-7 cells as evaluated by TUNEL assay and Annexin V/PI staining using FACS. By mechanism of action, ferrerol regulated the activation of p38 mitogen-activated protein kinase and altered the expression level of BAX, Bcl-2, and Poly ADP Ribose Polymerase in MCF-7 cells. In summary, our finding demonstrated that ferrerol has anti-cancer effect through regulating the activation and expression of apoptosis-related proteins in MCF-7 cells.

키워드

참고문헌

  1. Jung KW, Won YJ, Kong HJ, Lee ES (2018) Prediction of cancer incidence and mortality in Korea, 2018. Cancer Res Treat 50: 317 https://doi.org/10.4143/crt.2018.142
  2. Wu C, Ray RM, Lin MG, Gao DL, Horner NK, Nelson ZC, Lampe JW, Hu YW, Shannon J, Stalsberg H (2004) A case-control study of risk factors for fibrocystic breast conditions: Shanghai Nutrition and Breast Disease Study, China, 1995-2000. Am J Epidemiol 160: 945-960 https://doi.org/10.1093/aje/kwh318
  3. Woyengo T, Ramprasath V, Jones P (2009) Anticancer effects of phytosterols. Eur J Clin Nutr 63: 813-820 https://doi.org/10.1038/ejcn.2009.29
  4. Kim MY, Bo HH, Choi EO, Kwon DH, Kim HJ, Im Ahn K, Ji SY, Jeong J-W, Park S-H, Hong S-H (2018) Induction of apoptosis by Citrus unshiu Peel in human breast cancer MCF-7 cells: Involvement of ROSdependent activation of AMPK. Biol Pharm Bull 41: 713-721 https://doi.org/10.1248/bpb.b17-00898
  5. Longman AJ, Braden CJ, Mishel MH (1996) Side effects burden in women with breast cancer. Cancer Practice 4: 274-280
  6. Ansari L, Shiehzadeh F, Taherzadeh Z, Nikoofal-Sahlabadi S, Momtazi-Borojeni A, Sahebkar A, Eslami S (2017) The most prevalent side effects of pegylated liposomal doxorubicin monotherapy in women with metastatic breast cancer: a systematic review of clinical trials. Cancer Gene Ther 24: 189-193 https://doi.org/10.1038/cgt.2017.9
  7. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35: 495-516 https://doi.org/10.1080/01926230701320337
  8. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270: 1326-1331 https://doi.org/10.1126/science.270.5240.1326
  9. Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C (2003) A peptide inhibitor of c-Jun Nterminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 9: 1180-1186 https://doi.org/10.1038/nm911
  10. Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23: 2838-2849 doi:10.1038/sj.onc.1207556
  11. Peng YY, Liu FH, Ye JN (2004) Determination of Bioactive Flavonoids in Rhododendron Dauricum L. by Capillary Electrophoresis with Electrochemical Detection. Chromatographia 60: 597-602 doi:10.1365/s10337-004-0420-8
  12. Cao Y, Chu Q, Ye J (2004) Chromatographic and electrophoretic methods for pharmaceutically active compounds in Rhododendron dauricum. J Chromatogr B Analyt Technol Biomed Life Sci 812: 231-240 https://doi.org/10.1016/S1570-0232(04)00549-5
  13. Liu E, Liang T, Wang X, Ban S, Han L, Li Q (2015) Apoptosis induced by farrerol in human gastric cancer SGC-7901 cells through the mitochondrial-mediated pathway. Eur J Cancer Prev 24: 365-372 https://doi.org/10.1097/CEJ.0000000000000104
  14. Ci X, Chu X, Wei M, Yang X, Cai Q, Deng X (2012) Different effects of farrerol on an OVA-induced allergic asthma and LPS-induced acute lung injury. PLoS ONE 7
  15. Dai F, Gao L, Zhao Y, Wang C, Xie S (2016) Farrerol inhibited angiogenesis through Akt/mTOR, Erk and Jak2/Stat3 signal pathway. Phytomedicine 23: 686-693 https://doi.org/10.1016/j.phymed.2016.03.008
  16. Li Qy, Chen L, Zhu Yh, Zhang M, Wang Yp, Wang Mw (2011) Involvement of estrogen receptor-a in farrerol inhibition of rat thoracic aorta vascular smooth muscle cell proliferation. Acta Pharmacol Sin 32: 433-440 https://doi.org/10.1038/aps.2011.1
  17. Qiu J, Xiang H, Hu C, Wang Q, Dong J, Li H, Luo M, Wang J, Deng X (2011) Subinhibitory concentrations of farrerol reduce $\alpha$-toxin expression in Staphylococcus aureus. FEMS Microbiol Lett 315: 129-133 https://doi.org/10.1111/j.1574-6968.2010.02183.x
  18. Liu E, Li J, Shi S, Wang X, Liang T, Wu B, Li Q (2016) Sustained ERK activation-mediated proliferation inhibition of farrerol on human gastric carcinoma cell line by G0/G1-phase cell-cycle arrest. Eur J Cancer Prev 25: 490-499 https://doi.org/10.1097/CEJ.0000000000000212
  19. Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74: 597-608 https://doi.org/10.1016/0092-8674(93)90508-n
  20. Lu R, Serrero G (1999) Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. J Cell Physiol 179: 297-304 https://doi.org/10.1002/(SICI)1097-4652(199906)179:3<297::AID-JCP7>3.0.CO;2-P
  21. Wang W, Zhang X, Qin J-J, Voruganti S, Nag SA, Wang M-H, Wang H, Zhang R (2012) Natural product ginsenoside 25-OCH3-PPD inhibits breast cancer growth and metastasis through down-regulating MDM2. PLoS ONE 7
  22. Ledford H (2010) Complex synthesis yields breast-cancer therapy. Nature 468: 608-609 https://doi.org/10.1038/468608a
  23. Verma SP, Salamone E, Goldin B (1997) Curcumin and genistein, plant natural products, show synergistic inhibitory effects on the growth of human breast cancer MCF-7 cells induced by estrogenic pesticides. Biochem Biophys Res Commun 233: 692-696 https://doi.org/10.1006/bbrc.1997.6527