Table1_Autophagic Inhibition of Caveolin-1 by Compound Phyllanthus urinaria L. Activates Ubiquitination and Proteasome Degradation of β-catenin to Suppress Metastasis of Hepatitis B-Associated Hepatocellular Carcinoma.docx
Compound Phyllanthus urinaria L. (CP) is a traditional Chinese medicine (TCM) formula for cancer treatment in the clinic, particularly during progression of hepatitis B-associated hepatocellular carcinoma (HBV-associated HCC). Nevertheless, its anti-metastatic action and mechanisms are not well elucidated. In this study, CP was found to exert remarkable inhibitory effects on the proliferation, migration and invasion of HBV-associated HCC cells. The following network and biological analyses predicted that CP mainly targeted Caveolin-1 (Cav-1) to induce anti-metastatic effects, and Wnt/β-catenin pathway was one of the core mechanisms of CP action against HBV-associated HCC. Further experimental validation implied that Cav-1 overexpression promoted metastasis of HBV-associated HCC by stabilizing β-catenin, while CP administration induced autophagic degradation of Cav-1, activated the Akt/GSK3β-mediated proteasome degradation of β-catenin via ubiquitination activation, and subsequently attenuated the metastasis-promoting effect of Cav-1. In addition, the anti-cancer and anti-metastatic action of CP was further confirmed by in vivo and ex vivo experiments. It was found that CP inhibited the tumor growth and metastasis of HBV-associated HCC in both mice liver cancer xenograft and zebrafish xenotransplantation models. Taken together, our study not only highlights the novel function of CP formula in suppressing metastasis of HBV-associated HCC, but it also addresses the critical role of Cav-1 in mediating Akt/GSK3β/β-catenin axis to control the late-phase of cancer progression.
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References
- https://doi.org//10.1177/1010428317699127
- https://doi.org//10.1053/j.gastro.2004.02.014
- https://doi.org//10.1186/s12951-016-0217-6
- https://doi.org//10.1002/jcb.22251
- https://doi.org//10.1038/s41419-018-0795-3
- https://doi.org//10.1042/BJ20031259
- https://doi.org//10.3748/wjg.15.5669
- https://doi.org//10.1007/s00441-016-2453-3
- https://doi.org//10.1186/bcr3573
- https://doi.org//10.1111/j.1582-4934.2008.00622.x
- https://doi.org//10.1053/j.gastro.2011.12.061
- https://doi.org//10.1016/j.coph.2010.05.004
- https://doi.org//10.1016/j.mam.2006.08.005
- https://doi.org//10.1002/ijc.26092
- https://doi.org//10.1200/JCO.2006.08.9821
- https://doi.org//10.3389/fphar.2019.01185
- https://doi.org//10.1556/OH.2008.28313
- https://doi.org//10.6004/jnccn.2017.7024
- https://doi.org//10.3892/ol.2017.6108
- https://doi.org//10.3892/or.2016.4591
- https://doi.org//10.1097/SLA.0b013e318262b218
- https://doi.org//10.3389/fphar.2020.00414
- https://doi.org//10.1002/jmv.21117
- https://doi.org//10.1111/j.1572-0241.2008.01872.x
- https://doi.org//10.1111/j.1464-410x.2004.04604.x
- https://doi.org//10.1186/s12906-015-0792-3
- https://doi.org//10.1038/s41598-019-54705-x
- https://doi.org//10.1186/s13229-017-0168-2
- https://doi.org//10.1016/j.canlet.2009.04.010
- https://doi.org//10.1006/dbio.2002.0711
- https://doi.org//10.1158/1541-7786.MCR-09-0255
- https://doi.org//10.1155/2019/1635837
- https://doi.org//10.1002/hep.21053
- https://doi.org//10.1016/S1476-5586%2803%2980055-6
- https://doi.org//10.1016/j.jhep.2015.09.013
- https://doi.org//10.1016/j.canlet.2016.07.013
- https://doi.org//10.3748/wjg.v22.i33.7486
- https://doi.org//10.1093/carcin/bgn111
- https://doi.org//10.1006/meth.2001.1262
- https://doi.org//10.1038/s41419-018-0567-0
- https://doi.org//10.1016/j.devcel.2009.06.016
- https://doi.org//10.1016/j.cell.2007.06.009
- https://doi.org//10.1016/j.canlet.2018.12.003
- https://doi.org//10.1097/01.mog.0000218961.86182.8c
- https://doi.org//10.1242/jcs.009159
- https://doi.org//10.1158/0008-5472.can-03-1855
- https://doi.org//10.1002/mc.21927
- https://doi.org//10.1093/toxsci/kft158
- https://doi.org//10.1038/s41575-018-0075-9
- https://doi.org//10.1007/s11912-010-0094-3
- https://doi.org//10.4161/cc.10.21.17895
- https://doi.org//10.1002/hep.21543
- https://doi.org//10.1186/s12885-019-6479-2
- https://doi.org//10.1038/onc.2008.95
- https://doi.org//10.3390/ijms141020443
- https://doi.org//10.3892/ol.2015.3845
- https://doi.org//10.1016/j.biopha.2014.10.005
- https://doi.org//10.1152/ajpgi.00197.2019
- https://doi.org//10.1016/j.phrs.2015.09.019
- https://doi.org//10.1007/s11655-013-1320-7
- https://doi.org//10.18632/oncotarget.26103
- https://doi.org//10.7150/thno.15083
- https://doi.org//10.1093/carcin/bgu187
- https://doi.org//10.1016/j.biopha.2019.109519
- https://doi.org//10.3390/cancers11070910
- https://doi.org//10.3389/fonc.2020.00046
- https://doi.org//10.1016/j.bbrc.2016.03.024
- https://doi.org//10.3892/ijo.2013.2107
- https://doi.org//10.3892/or.2017.5721
- https://doi.org//10.1038/onc.2012.40
- https://doi.org//10.1371/journal.pone.0035331
- https://doi.org//10.1002/hep.21473
- https://doi.org//10.1186/s12967-020-02262-7
- https://doi.org//10.1007/bf01247463
- https://doi.org//10.1038/nrd1606