Root Bark of Morus alba L. and Its Bioactive Ingredient, Ursolic Acid, Suppress the Proliferation of Multiple Myeloma Cells by Inhibiting Wnt/β-Catenin Pathway
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The root bark of Morus alba L. has cytotoxic activity against several types of cancer cells. However, little is known about its chemopreventive mechanisms and bioactive metabolites. In this study, we showed that M. alba L. root bark extracts (MRBE) suppressed β-catenin response transcription (CRT), which is aberrantly activated in various cancers, by promoting the degradation of β-catenin. In addition, MRBE repressed the expression of the β-catenin/T-cell factor (TCF)-dependent genes, cmyc and cyclin D1, thus inhibiting the proliferation of RPMI-8226 multiple myeloma (MM) cells. MRBE induced apoptosis in MM cells, as evidenced by the increase in the population of annexin VFITC- positive cells and caspase-3/7 activity. We identified ursolic acid in MRBE through LC/mass spectrum (MS) and observed that it also decreased intracellular β-catenin, c-myc, and cyclin D1 levels. Furthermore, it suppressed the proliferation of RPMI-8226 cells by stimulating cell cycle arrest and apoptosis. These findings suggest that MRBE and its active ingredient, ursolic acid, exert antiproliferative activity by promoting the degradation of β-catenin and may have significant chemopreventive potential against MM.
Abstract
The root bark of Morus alba L. has cytotoxic activity against several types of cancer cells. However, little is known about its chemopreventive mechanisms and bioactive metabolites. In this study, we showed that M. alba L. root bark extracts (MRBE) suppressed β-catenin response transcription (CRT), which is aberrantly activated in various cancers, by promoting the degradation of β-catenin. In addition, MRBE repressed the expression of the β-catenin/T-cell factor (TCF)-dependent genes, cmyc and cyclin D1, thus inhibiting the proliferation of RPMI-8226 multiple myeloma (MM) cells. MRBE induced apoptosis in MM cells, as evidenced by the increase in the population of annexin VFITC- positive cells and caspase-3/7 activity. We identified ursolic acid in MRBE through LC/mass spectrum (MS) and observed that it also decreased intracellular β-catenin, c-myc, and cyclin D1 levels. Furthermore, it suppressed the proliferation of RPMI-8226 cells by stimulating cell cycle arrest and apoptosis. These findings suggest that MRBE and its active ingredient, ursolic acid, exert antiproliferative activity by promoting the degradation of β-catenin and may have significant chemopreventive potential against MM.
참고문헌 (39)
- Group IMW, "Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders : a report of the International Myeloma Working Group", Br. J. Haematol, 121, pp.749~757 (2003)
- Sukhdeo K, "Targeting the β-catenin", TCF transcriptional complex in the treatment of multiple myeloma, 2007, pp.104, 7516~7521
- Latres E, "The human F box protein β-Trcp associates with the Cul1", Skp1 complex and regulates the stability of β-catenin, 1999, pp.18, 849~854
- Derksen PW, "Illegitimate WNT signaling promotes proliferation of multiple myeloma cells", Proc. Natl. Acad. Sci. USA, 101, pp.6122~6127 (2004)
- He T-C, "Identification of c-MYC as a target of the APC pathway", Science, 281, pp.1509~1512 (1998)
- He T-C, "PPARδ is an APC-regulated target of nonsteroidal anti-inflammatory drugs", Cell, 99, pp.335~345 (1999)
- Tetsu O, "β-Catenin regulates expression of cyclin D1 in colon carcinoma cells", Nature, 398, pp.422~426 (1999)
- Takahashi M, "Identification of membrane-type matrix metalloproteinase-1 as a target of the β-catenin", Tcf4 complex in human colorectal cancers, 2002, pp.21, 5861~5867
- Eo HJ, "Anti-inflammatory and anti-cancer activity of mulberry (Morus alba L.) root bark", BMC Complement. Altern. Med, 14, pp.1200~ (2014)
- Sang-YunNam, "Cortex Mori Extract Induces Cancer Cell Apoptosis Through Inhibition of Microtubule Assembly", Archives of Pharmacal Research, 25(3), pp.191~196 (2002), 대한약학회
- Park S-H, "Role of autophagy in apoptosis induction by methylene chloride extracts of Mori cortex in NCI-H460 human lung carcinoma cells", Int. J. Oncol, 40, pp.1929~1940 (2012)
- Min T-R, "The root bark of Morus alba L. suppressed the migration of human non-smallcell lung cancer cells through inhibition of epithelial–mesenchymal transition mediated by STAT3 and Src", Int. J. Mol. Sci, 20, pp.2244~ (2019)
- Shen M, "Betulinic acid induces ROS-dependent apoptosis and S-phase arrest by inhibiting the NF-κB pathway in human multiple myeloma", Oxid. Med. Cell. Longev, 2019, pp.5083158~ (2019)
- Ryu M-J, "Natural derivatives of curcumin attenuate the Wnt", β-catenin pathway through down-regulation of the transcriptional coactivator p300, 2008, pp.377, 1304~1308
- Dignam JD, "Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei", Nucleic Acids Res, 11, pp.1475~1489 (1983)
- Park S, "CCAAT", enhancer-binding protein-β functions as a negative regulator of Wnt, Cell Death Dis, pp.2018, 9[DOI]
- Lee DY, "High quality metabolomic data for Chlamydomonas reinhardtii", Plant Methods, 4, pp.7~ (2008)
- Son Y, "Longan fruit increase bone mineral density in zebrafish and ovariectomized rat by suppressing RANKL-induced osteoclast differentiation", Phytomedicine, 59, pp.152910~ (2019)
- He X, "LDL receptor-related proteins 5 and 6 in Wnt", β-catenin signaling : arrows point the way, 2004, pp.131, 1663~1677
- Liu C, "Control of β-catenin phosphorylation", degradation by a dual-kinase mechanism, 2002, pp.108, 837~847
- Klein PS, "A molecular mechanism for the effect of lithium on development", Proc. Natl. Acad. Sci. USA, 93, pp.8455~8459 (1996)
- Chapman MA, "Initial genome sequencing and analysis of multiple myeloma", Nature, 471, pp.467~472 (2011)
- Schmeel LC, "Targeting the Wnt", beta-catenin pathway in multiple myeloma, 2013, pp.33, 4719~4726
- Chan EW-C, "Phytochemistry, pharmacology, and clinical trials of Morus alba", Chin. J. Nat. Med, 14, pp.17~30 (2016)
- Woźniak Ł, "Ursolic acid-a pentacyclic triterpenoid with a wide spectrum of pharmacological activities", Molecules, 20, pp.20614~20641 (2015)
- Kim J-H, "Ursolic acid and its natural derivative corosolic acid suppress the proliferation of APC-mutated colon cancer cells through promotion of β-catenin degradation", Food Chem. Toxicol, 67, pp.87~95 (2014)
- Zhang RX, "Ursolic acid inhibits proliferation and induces apoptosis by inactivating Wnt", β-catenin signaling in human osteosarcoma cells, 2016, pp.49, 1973~1982
- Park J-H, "Inhibition of Wnt", β-catenin signaling mediates ursolic acidinduced apoptosis in PC-3 prostate cancer cells, 2013, pp.65, 1366~1374
- Wodarz A, "Mechanisms of Wnt signaling in development", Ann. Rev. Cell Dev. Biol, 14, pp.59~88 (1998)
- Aberle H, "β-catenin is a target for the ubiquitin–proteasome pathway", EMBO J, 16, pp.3797~3804 (1997)
- Miller JR, "The Wnts", Genome Biol, 3 (2001)
- Hart M, "The F-box protein β-TrCP associates with phosphorylated β-catenin and regulates its activity in the cell", Curr. Biol, 9, pp.207~211 (1999)
- Gwak J, "Protein-kinase-C-mediated β-catenin phosphorylation negatively regulates the Wnt", β-catenin pathway, 2006, pp.119, 4702~4709
- Gwak J, "Stimulation of protein kinase Cα suppresses colon cancer cell proliferation by down-regulation of β-catenin", J. Cell. Mol. Med, 13, pp.2171~2180 (2009)
- Mandal S, "Inhibition of breast cancer stem-like cells by a triterpenoid, ursolic acid, via activation of Wnt antagonist, sFRP4 and suppression of miRNA-499a-5p", Life Sci, 265, pp.118854~ (2021)
- Spaan I, "Wnt signaling in multiple myeloma : a central player in disease with therapeutic potential", J. Hematol. Ocol, 11, pp.67~ (2018)
- Park S, "Ilimaquinone and ethylsmenoquinone, marine sponge metabolites, suppress the proliferation of multiple myeloma cells by down-regulating the level of β-catenin", Mar. Drugs, 12, pp.3231~3244 (2014)
- Grigson ER, "Canonical Wnt pathway inhibitor ICG-001 induces cytotoxicity of multiple myeloma cells in Wnt-independent manner", PLoS One, 10, pp.e0117693~ (2015)
- Sook SH, "Reactive oxygen species-mediated activation of AMP-activated protein kinase and c-Jun N-terminal kinase plays a critical role in beta-sitosterol-induced apoptosis in multiple myeloma U266 cells", Phytother. Res, 28, pp.387~394 (2014)
