독활 에탄올 추출물의 대장암 세포에서 Cyclin D1 단백질 분해 유도를 통한 세포 생육 억제활성 = Anti-proliferative Activity of Ethanol Extracts of Root of Aralia cordata var. continentalis through Proteasomal Degradation of Cyclin D1 in Human Colorectal Cancer Cells

다국어 초록 (Multilingual Abstract)

Background: In this study, we evaluated the anti-cancer activity and potential molecular mechanism of 70% ethanol extracts of the root of Aralia cordata var. continentalis (Kitagawa) Y. C. Chu (RAc-E70) against human colorectal cancer cells. Methods and Results: RAc-E70 suppressed the proliferation of the human colorectal cancer cell lines, HCT116 and SW480. Although RAc-E70 reduction cyclin D1 expression at the protein and mRNA levels, RAc-E70-induced reduction in cyclin D1 protein level occurred more dramatically than that of cyclin D1 mRNA. The RAc-E70-induced downregulation of cyclin D1 expression was attenuated in the presence of MG132. Additionally, RAc-E70 reduced HA-cyclin D1 levels in HCT116 cells transfected with HA-tagged wild type-cyclin D1 expression vector. RAc-E70-mediated cyclin D1 degradation was blocked in the presence of LiCl, a $GSK3{\beta}$ inhibitorbut, but not PD98059, an ERK1/2 inhibitor and SB203580, a p38 inhibitor. Furthermore, RAc-E70 phosphorylated cyclin D1 at threonine-286 (T286), and LiCl-induced $GSK3{\beta}$ inhibition reduced the RAc-E70-mediated phosphorylation of cyclin D1 at T286. Conclusions: Our results suggested that RAc-E70 may downregulate cyclin D1 expression as a potential anti-cancer target through $GSK3{\beta}$-dependent cyclin D1 degradation. Based on these findings, RAc-E70 maybe a potential candidate for the development of chemopreventive or therapeutic agents for human colorectal cancer.

참고문헌 (Reference)

1 양선아, "독활의 항혈소판 및 항산화 효과" 한국생명과학회 18 (18): 357-362, 2008

2 한완수, "독활 뿌리 추출물에서 항균물질의 분리 및 항균성" 한국약용작물학회 13 (13): 182-185, 2005

3 박봉기, "국내에 보고된 한국 한의학의 암치료 임상연구에 대한 계통적 고찰" 대한한방내과학회 29 (29): 1061-1074, 2008

4 Thoms HC, "p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells" 67 : 1660-1669, 2007

5 Alao JP, "The regulation of cyclin D1 degradation : Roles in cancer development and the potential for therapeutic invention" 6 : 24-39, 2007

6 Langenfeld J, "Posttranslational regulation of cyclin D1 by retinoic acid : A chemoprevention mechanism" 94 : 12070-12074, 1997

7 Wang H, "Plants against cancer : A review on natural phytochemicals in preventing and treating cancers and their druggability" 12 : 1281-1305, 2012

8 Kessler RC, "Long-term trends in the use of complementary and alternative medical therapies in the United States" 135 : 262-268, 2001

9 Qin A, "Inhibition of STAT3/cyclin D1 pathway promotes chemotherapeutic sensitivity of colorectal caner" 457 : 681-687, 2015

10 Alao JP, "Histone deacetylase inhibitor, trichostatin A induces ubiquitin-dependent cyclin D1 degradation in MCF-7breast cancer cells" 5 : 8-18, 2006

11 Alao JP, "Histone deacetylase inhibitor trichostatin A represses estrogen receptor α-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines" 10 : 8094-8104, 2004

12 Diehl JA, "Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization" 12 : 3499-3511, 1998

13 Park HJ, "Effects of Aralia continentalis on hyperalgesia with peripheral inflammation" 19 : 511-513, 2005

14 Park SH, "Cytotoxic polyacetylenes from Aralia cordata" 39 : 681-688, 1995

15 Russell A, "Cyclin D1 and D3 associate with the SCF complex and are coordinately elevated in breast cancer" 18 : 1983-1991, 1999

16 Musgrove EA, "Cyclin D as a therapeutic target in cancer" 11 : 558-572, 2011

17 Jeong SI, "Continentalic acid from Aralia continentalis shows activity against methicilinresistant Staphylococcus aureus" 20 : 511-514, 2006

18 Gopalakrishnan N, "Colocalization of β-catenin with Notch intracellular domain in colon cancer : A possible role of Notch1 signaling in activation of cyclin D1-mediated cell proliferation" 396 : 281-293, 2014

19 정규원, "Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2014" 대한암학회 49 (49): 292-305, 2017

20 Dobos GJ, "Are national quality standards for traditional Chinese herbal medicine sufficient? : Current governmental regulations for traditional Chinese herbal medicine in certain Western countries and China as the Eastern origin country" 13 : 183-190, 2005

21 Gillett C, "Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining" 54 : 1812-1817, 1994

22 Okabe H, "A critical role for FBXW8 and MAPK in cyclin D1 degradation and cancer cell proliferation" 1-12, 2006