유방암세포에서 LATS1/2 활성에 의한 당귀 추출물의 항암효과
Anti-tumorigenic Effects of Angelica gigase Nakai Extract on MBA-MB-231 through Regulating Lats1/2 Activation
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초록
The Hippo-YAP signaling pathway is critical for cell proliferation, survival, and self-renewal in both Drosophila and mammals. Disorder of Hippo-YAP pathway leads to tumor development, progression and poor prognosis in various cancers. YAP/TAZ are the key downstream effectors of the Hippo pathway and they can be inhibited through LATS1/2, core kinases in the Hippo pathway, mediated phosphorylation. In this study, we investigated the effect of Angelica gigas Nakai extract (AGNE) on Hippo-YAP/TAZ pathway. First, ANGE induced YAP/TAZ phosphorylation and dissociation of the YAP/TAZ-TEAD transcription complex. By qRT-PCR, we found that ANGE inhibits the expression of YAP/TAZ-TEAD target gene, CTGF and CYR61. In addition, the transcriptional activity of YAP/TAZ was not suppressed significantly in LATS1/2 double-knockout (DKO) cells by ANGE compared to LATS1/2 wild-type (WT) cells, which means AGNE inhibits YAP/TAZ signaling through direct action on LATS1/2. Further, it was confirmed that AGNE-induced activation of LATS1/2 inhibited the migration potential of the vector-expressing cells by suppressing YAP/TAZ activity. The reduced migration potential was restored in active YAP-TEAD expressing cells. Taken together, the results of this study indicate that ANGE downregulates YAP/TAZ signaling in cells through the activation of LATS1/2.
Abstract
The Hippo-YAP signaling pathway is critical for cell proliferation, survival, and self-renewal in both Drosophila and mammals. Disorder of Hippo-YAP pathway leads to tumor development, progression and poor prognosis in various cancers. YAP/TAZ are the key downstream effectors of the Hippo pathway and they can be inhibited through LATS1/2, core kinases in the Hippo pathway, mediated phosphorylation. In this study, we investigated the effect of Angelica gigas Nakai extract (AGNE) on Hippo-YAP/TAZ pathway. First, ANGE induced YAP/TAZ phosphorylation and dissociation of the YAP/TAZ-TEAD transcription complex. By qRT-PCR, we found that ANGE inhibits the expression of YAP/TAZ-TEAD target gene, CTGF and CYR61. In addition, the transcriptional activity of YAP/TAZ was not suppressed significantly in LATS1/2 double-knockout (DKO) cells by ANGE compared to LATS1/2 wild-type (WT) cells, which means AGNE inhibits YAP/TAZ signaling through direct action on LATS1/2. Further, it was confirmed that AGNE-induced activation of LATS1/2 inhibited the migration potential of the vector-expressing cells by suppressing YAP/TAZ activity. The reduced migration potential was restored in active YAP-TEAD expressing cells. Taken together, the results of this study indicate that ANGE downregulates YAP/TAZ signaling in cells through the activation of LATS1/2.
참고문헌 (29)
- Dong J, "Elucidation of a universal size-control mechanism in Drosophila and mammals", Cell, 130(6), pp.1120~1133 (2007)
- Pan D, "The hippo signaling pathway in development and cancer", Developmental cell, 19(4), pp.491~505 (2010)
- Harvey KF, "The Hippo pathway and human cancer", Nature reviews Cancer, 13(4), pp.246~257 (2013)
- Johnson R, "The two faces of Hippo : targeting the Hippo pathway for regenerative medicine and cancer treatment", Nature reviews Drug discovery, 13(1), pp.63~79 (2014)
- Mo JS, "The Hippo signaling pathway in stem cell biology and cancer", EMBO reports, 15(6), pp.642~656 (2014)
- Chan EH, "The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1", Oncogene, 24(12), pp.2076~2086 (2005)
- Camargo FD, "YAP1 increases organ size and expands undifferentiated progenitor cells", Current biology : CB, 17(23), pp.2054~2060 (2007)
- Hao Y, "Tumor suppressor LATS1 is a negative regulator of oncogene YAP", The Journal of biological chemistry, 283(9), pp.5496~5509 (2008)
- Zhao B, "TEAD mediates YAP-dependent gene induction and growth control", Genes & development, 22(14), pp.1962~1971 (2008)
- Yu FX, "The Hippo pathway : regulators and regulations", Genes & development, 27(4), pp.355~371 (2013)
- Piccolo S, "The biology of YAP", TAZ : hippo signaling and beyond, 2014, pp.94(4), 1287~1312
- Hansen CG, "YAP and TAZ : a nexus for Hippo signaling and beyond", Trends in cell biology, 25(9), pp.499~513 (2015)
- Plouffe SW, "Disease implications of the Hippo", YAP pathway, 2015, pp.21(4), 212~222
- Son SH, "Decursin and decursinol from Angelica gigas inhibit the lung metastasis of murine colon carcinoma", Phytotherapy research : PTR, 25(7), pp.959~964 (2011)
- Wan YQ, "Determination of trace elements in danggui blood-supplementing decoction by ICP-AES", Guang pu xue yu guang pu fen xi = Guang pu, 27(1), pp.160~164 (2007)
- Kim MR, "Identification of volatile components in Angelica species using supercritical-CO2 fluid extraction and solid phase microextraction coupled to gas chromatography-mass spectrometry", Biomedical chromatography : BMC, 20(11), pp.1267~1273 (2006)
- Kim MR, "Determination of volatile flavor components in danggui cultivars by solvent free injection and hydrodistillation followed by gas chromatographic-mass spectrometric analysis", Journal of chromatography A, 1116(1-2), pp.259~264 (2006)
- Heo BG, "Antiproliferative activity of Korean wild vegetables on different human tumor cell lines", Plant foods for human nutrition, 64(4), pp.257~263 (2009)
- Choi HS, "Anti-inflammatory and anti-proliferative effect of herbal medicines (APR) in RAW264.7 cells", Molecular medicine reports, 9(5), pp.1569~1574 (2014)
- 장자영, "An ethanolic extract of Angelica gigas improves atherosclerosis by inhibiting vascular smooth muscle cell proliferation", Laboratory Animal Research, 30(2), pp.84~89 (2014), 한국실험동물학회
- Cho JH, "Anti-Inflammatory Effect of Angelica gigas via Heme Oxygenase(HO)-1 Expression", Nutrients, 7(6), pp.4862~4874 (2015)
- Ku SK, "Ameliorating effects of herbal formula hemomine on experimental subacute hemorrhagic anemia in rats", Journal of ethnopharmacology, 198, pp.205~213 (2017)
- Kim JY, "Angelan isolated from Angelica gigas Nakai induces dendritic cell maturation through toll-like receptor 4", International immunopharmacology, 7(1), pp.78~87 (2007)
- Yim D, "A novel anticancer agent, decursin, induces G1 arrest and apoptosis in human prostate carcinoma cells", Cancer research, 65(3), pp.1035~1044 (2005)
- Mo JS, "Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway", Nature cell biology, 17(4), pp.500~510 (2015)
- 모정순, "The role of extracellular biophysical cues in modulating the Hippo-YAP pathway", BMB Reports, 50(2), pp.71~78 (2017), 생화학분자생물학회
- Cordenonsi M, "The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells", Cell, 147(4), pp.759~772 (2011)
- Xin M, "Hippo pathway effector Yap promotes cardiac regeneration", Proceedings of the National Academy of Sciences of the United States of America, 110(34), pp.13839~13844 (2013)
- Bartucci M, "TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells", Oncogene, 34(6), pp.681~690 (2015)