Cyclizing-berberine A35 induces G2/M arrest and apoptosis by activating YAP phosphorylation (Ser127)
Tóm tắt
A35 is a novel synthetic cyclizing-berberine recently patented as an antitumor compound. Based on its dual targeting topoisomerase (top) activity, A35 might overcome the resistance of single-target top inhibitors and has no cardiac toxicity for not targeting top2β. In this study we further explored the biological effects and mechanisms of A35. Antitumor activity of A35 was evaluated by SRB and colony formation assay. G2/M phase arrest (especially M) and first damage of M-phase cells were investigated by flow cytometry, cytogenetic analysis, immunofluorescence, co-immunoprecipitation and WB. The key role of phospho-YAP (Ser127) in decreasing YAP nuclear localization, subsequent G2/M arrest and proliferation inhibition were explored by YAP1−/− cells, mutated Ser127 YAP construct (Ser127A) and TUNEL. G2/M arrest induced by A35 was independent of p53. M phase cells at low dose were firstly damaged and most damaged-cells accumulated in M phase, and that was a result of preferring targeting top2α by A35, as top2α is essential to push M phase into next phase, and targeting top2α induced cells arrested at M phase. A35 decreased YAP1 nuclear localization by activating YAP phosphorylation (Ser127) which subsequently regulated the transcription of YAP target genes associated with growth and cycle regulation to induce G2/M arrest and growth inhibition. Our studies suggested the mechanism of G2/M arrest induced by A35 and a novel role of YAP1 (Ser127) in G2/M arrest. As a dual topoisomerase inhibitor characterized by no cardiac toxicity, A35 is a promising topoisomerase anticancer agent and worthy of further development in future.
Tài liệu tham khảo
citation_journal_title=Cancer Lett; citation_title=The anti-inflammatory potential of berberine in vitro and in vivo; citation_author=CL Kuo, CW Chi, TY Liu; citation_volume=203; citation_issue=2; citation_publication_date=2004; citation_pages=127-137; citation_doi=10.1016/j.canlet.2003.09.002; citation_id=CR1
citation_journal_title=Arch Toxicol; citation_title=Inhibitory effect of berberine on tert-butyl hydroperoxide-induced oxidative damage in rat liver; citation_author=JM Hwang, CJ Wang, FP Chou, TH Tseng, YS Hsieh, WL Lin, CY Chu; citation_volume=76; citation_issue=11; citation_publication_date=2002; citation_pages=664-670; citation_doi=10.1007/s00204-002-0351-9; citation_id=CR2
citation_journal_title=Cancer Lett; citation_title=Berberine-antiproliferative activity in vitro and induction of apoptosis/necrosis of the U937 and B16 cells; citation_author=S Letasiova, S Jantova, L Cipak, M Muckova; citation_volume=239; citation_issue=2; citation_publication_date=2006; citation_pages=254-262; citation_doi=10.1016/j.canlet.2005.08.024; citation_id=CR3
citation_journal_title=World J Gastroenterol; citation_title=Berberine induces cell cycle arrest and apoptosis in human gastric carcinoma SNU-5 cell line; citation_author=JP Lin, JS Yang, JH Lee, WT Hsieh, JG Chung; citation_volume=12; citation_issue=1; citation_publication_date=2006; citation_pages=21-28; citation_doi=10.3748/wjg.v12.i1.21; citation_id=CR4
citation_journal_title=Int J Med Sci; citation_title=Effect of YAP inhibition on human leukemia HL-60 cells; citation_author=M Chen, J Wang, SF Yao, Y Zhao, L Liu, LW Li, T Xu, LG Gan, CL Xiao, ZL Shan; citation_volume=14; citation_issue=9; citation_publication_date=2017; citation_pages=902-910; citation_doi=10.7150/ijms.19965; citation_id=CR5
citation_journal_title=Int J Med Sci; citation_title=Knockdown of yes-associated protein induces the apoptosis while inhibits the proliferation of human periodontal ligament stem cells through crosstalk between Erk and Bcl-2 signaling pathways; citation_author=Y Wen, Y Ji, Y Zhang, B Jiang, C Tang, Q Wang, X Chen, L Jia, W Gu, X Xu; citation_volume=14; citation_issue=12; citation_publication_date=2017; citation_pages=1231-1240; citation_doi=10.7150/ijms.20504; citation_id=CR6
citation_journal_title=Biochem Biophys Res Commun; citation_title=TEAD4-YAP interaction regulates tumoral growth by controlling cell-cycle arrest at the G1 phase; citation_author=S Takeuchi, A Kasamatsu, M Yamatoji, D Nakashima, Y Endo-Sakamoto, N Koide, T Takahara, T Shimizu, M Iyoda, K Ogawara; citation_volume=486; citation_issue=2; citation_publication_date=2017; citation_pages=385-390; citation_doi=10.1016/j.bbrc.2017.03.050; citation_id=CR7
citation_journal_title=elife; citation_title=YAP controls retinal stem cell DNA replication timing and genomic stability; citation_author=P Cabochette, G Vega-Lopez, J Bitard, K Parain, R Chemouny, C Masson, C Borday, M Hedderich, KA Henningfeld, M Locker; citation_volume=4; citation_publication_date=2015; citation_pages=e08488; citation_doi=10.7554/eLife.08488; citation_id=CR8
citation_journal_title=PLoS One; citation_title=YAP regulates S-phase entry in endothelial cells; citation_author=Z Shen, BZ Stanger; citation_volume=10; citation_issue=1; citation_publication_date=2015; citation_pages=e0117522; citation_doi=10.1371/journal.pone.0117522; citation_id=CR9
citation_journal_title=Cancer Res; citation_title=CDK1 phosphorylation of YAP promotes mitotic defects and cell motility and is essential for neoplastic transformation; citation_author=S Yang, L Zhang, M Liu, R Chong, SJ Ding, Y Chen, J Dong; citation_volume=73; citation_issue=22; citation_publication_date=2013; citation_pages=6722-6733; citation_doi=10.1158/0008-5472.CAN-13-2049; citation_id=CR10
citation_journal_title=Eur J Med Chem; citation_title=Discovery, synthesis and biological evaluation of cycloprotoberberine derivatives as potential antitumor agents; citation_author=YB Li, WL Zhao, YX Wang, CX Zhang, JD Jiang, CW Bi, S Tang, RX Chen, RG Shao, DQ Song; citation_volume=68; citation_publication_date=2013; citation_pages=463-472; citation_doi=10.1016/j.ejmech.2013.07.026; citation_id=CR11
citation_journal_title=Cell Death Differ; citation_title=Mitotic catastrophe is the predominant response to histone acetyltransferase depletion; citation_author=GH Ha, HS Kim, CG Lee, HY Park, EJ Kim, HJ Shin, JC Lee, KW Lee, CW Lee; citation_volume=16; citation_issue=3; citation_publication_date=2009; citation_pages=483-497; citation_doi=10.1038/cdd.2008.182; citation_id=CR12
citation_journal_title=Mol Cancer Ther; citation_title=Inhibition of topoisomerase IIalpha and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials; citation_author=L Guo, X Liu, K Nishikawa, W Plunkett; citation_volume=6; citation_issue=5; citation_publication_date=2007; citation_pages=1501-1508; citation_doi=10.1158/1535-7163.MCT-06-0780; citation_id=CR13
citation_journal_title=Chin Sci Bull; citation_title=Myofibrillogenesis regulator-1 promotes cell adhesion and migration in human hepatoma cells; citation_author=W Zhao, H He, K Ren, H Zhang, Y Chen, R Shao; citation_volume=58; citation_issue=24; citation_publication_date=2013; citation_pages=3007-3014; citation_doi=10.1007/s11434-013-5933-9; citation_id=CR14
citation_journal_title=Onco Targets Ther; citation_title=Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage; citation_author=W Zhao, C Zhang, C Bi, C Ye, D Song, X Liu, R Shao; citation_volume=9; citation_publication_date=2016; citation_pages=2805-2817; citation_doi=10.2147/OTT.S103671; citation_id=CR15
citation_journal_title=Oncotarget; citation_title=The dual topoisomerase inhibitor A35 preferentially and specially targets topoisomerase 2alpha by enhancing pre-strand and post-strand cleavage and inhibiting DNA religation; citation_author=W Zhao, G Jiang, C Bi, Y Li, J Liu, C Ye, H He, L Li, D Song, R Shao; citation_volume=6; citation_issue=35; citation_publication_date=2015; citation_pages=37871-37894; citation_doi=10.18632/oncotarget.5680; citation_id=CR16
citation_journal_title=Radiat Oncol; citation_title=CFAssay: statistical analysis of the colony formation assay; citation_author=H Braselmann, A Michna, J Hess, K Unger; citation_volume=10; citation_publication_date=2015; citation_pages=223; citation_doi=10.1186/s13014-015-0529-y; citation_id=CR17
citation_journal_title=BioTechniques; citation_title=Increased efficiency for performing colony formation assays in 96-well plates: novel applications to combination therapies and high-throughput screening; citation_author=D Katz, E Ito, KS Lau, JD Mocanu, C Bastianutto, AD Schimmer, FF Liu; citation_volume=44; citation_issue=2; citation_publication_date=2008; citation_pages=ix-xiv; citation_doi=10.2144/000112757; citation_id=CR18
citation_journal_title=Am J Physiol Heart Circ Physiol; citation_title=ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes; citation_author=J Liu, W Mao, B Ding, CS Liang; citation_volume=295; citation_issue=5; citation_publication_date=2008; citation_pages=H1956-H1965; citation_doi=10.1152/ajpheart.00407.2008; citation_id=CR19
citation_journal_title=Science; citation_title=Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II; citation_author=KM Tewey, TC Rowe, L Yang, BD Halligan, LF Liu; citation_volume=226; citation_issue=4673; citation_publication_date=1984; citation_pages=466-468; citation_doi=10.1126/science.6093249; citation_id=CR20
citation_journal_title=Nature; citation_title=The DNA damage response: putting checkpoints in perspective; citation_author=BB Zhou, SJ Elledge; citation_volume=408; citation_issue=6811; citation_publication_date=2000; citation_pages=433-439; citation_doi=10.1038/35044005; citation_id=CR21
citation_journal_title=Mol Cancer Ther; citation_title=Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells; citation_author=SK Mantena, SD Sharma, SK Katiyar; citation_volume=5; citation_issue=2; citation_publication_date=2006; citation_pages=296-308; citation_doi=10.1158/1535-7163.MCT-05-0448; citation_id=CR22
citation_journal_title=J Biol Chem; citation_title=DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139; citation_author=EP Rogakou, DR Pilch, AH Orr, VS Ivanova, WM Bonner; citation_volume=273; citation_issue=10; citation_publication_date=1998; citation_pages=5858-5868; citation_doi=10.1074/jbc.273.10.5858; citation_id=CR23
citation_journal_title=Methods Mol Biol; citation_title=Histone H2AX phosphorylation: a marker for DNA damage; citation_author=A Sharma, K Singh, A Almasan; citation_volume=920; citation_publication_date=2012; citation_pages=613-626; citation_doi=10.1007/978-1-61779-998-3_40; citation_id=CR24
citation_journal_title=In Vivo; citation_title=Gamma-H2AX - a novel biomarker for DNA double-strand breaks; citation_author=LJ Kuo, LX Yang; citation_volume=22; citation_issue=3; citation_publication_date=2008; citation_pages=305-309; citation_id=CR25
citation_journal_title=Stem Cells; citation_title=Controlling the survival of human pluripotent stem cells by small molecule-based targeting of topoisomerase II alpha; citation_author=U Ben-David, IG Cowell, CA Austin, N Benvenisty; citation_volume=33; citation_issue=3; citation_publication_date=2014; citation_pages=1013-9; citation_doi=10.1002/stem.1888; citation_id=CR26
citation_journal_title=Oncogene; citation_title=Topoisomerase IIalpha in chromosome instability and personalized cancer therapy; citation_author=T Chen, Y Sun, P Ji, S Kopetz, W Zhang; citation_volume=34; citation_issue=31; citation_publication_date=2014; citation_pages=4019-31; citation_doi=10.1038/onc.2014.332; citation_id=CR27
citation_journal_title=J Biol Chem; citation_title=The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01; citation_author=PR Graves, L Yu, JK Schwarz, J Gales, EA Sausville, PM O'Connor, H Piwnica-Worms; citation_volume=275; citation_issue=8; citation_publication_date=2000; citation_pages=5600-5605; citation_doi=10.1074/jbc.275.8.5600; citation_id=CR28
citation_journal_title=Blood; citation_title=Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial; citation_author=D Sampath, J Cortes, Z Estrov, M Du, Z Shi, M Andreeff, V Gandhi, W Plunkett; citation_volume=107; citation_issue=6; citation_publication_date=2006; citation_pages=2517-2524; citation_doi=10.1182/blood-2005-08-3351; citation_id=CR29
citation_journal_title=Ann Oncol; citation_title=Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret hospital phase II consortium study; citation_author=SJ Hotte, A Oza, EW Winquist, M Moore, EX Chen, S Brown, GR Pond, JE Dancey, HW Hirte; citation_volume=17; citation_issue=2; citation_publication_date=2006; citation_pages=334-340; citation_doi=10.1093/annonc/mdj076; citation_id=CR30
citation_journal_title=EMBO Rep; citation_title=Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization; citation_author=S Moon, W Kim, S Kim, Y Kim, Y Song, O Bilousov, J Kim, T Lee, B Cha, M Kim; citation_volume=18; citation_issue=1; citation_publication_date=2017; citation_pages=61-71; citation_doi=10.15252/embr.201642683; citation_id=CR31
citation_journal_title=Cell Death Differ; citation_title=C-Abl antagonizes the YAP oncogenic function; citation_author=R Keshet, J Adler, I Ricardo Lax, M Shanzer, Z Porat, N Reuven, Y Shaul; citation_volume=22; citation_issue=6; citation_publication_date=2015; citation_pages=935-945; citation_doi=10.1038/cdd.2014.182; citation_id=CR32
citation_journal_title=Nat Med; citation_title=Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers; citation_author=F Cottini, T Hideshima, C Xu, M Sattler, M Dori, L Agnelli, E ten Hacken, MT Bertilaccio, E Antonini, A Neri; citation_volume=20; citation_issue=6; citation_publication_date=2014; citation_pages=599-606; citation_doi=10.1038/nm.3562; citation_id=CR33
citation_journal_title=Blood Cancer J; citation_title=MR-1 blocks the megakaryocytic differentiation and transition of CML from chronic phase to blast crisis through MEK dephosphorylation; citation_author=W Zhao, H He, K Ren, B Li, H Zhang, Y Lin, RG Shao; citation_volume=3; citation_publication_date=2013; citation_pages=e107; citation_doi=10.1038/bcj.2013.5; citation_id=CR34
citation_journal_title=Nat Rev Cancer; citation_title=The hippo pathway and human cancer; citation_author=KF Harvey, X Zhang, DM Thomas; citation_volume=13; citation_issue=4; citation_publication_date=2013; citation_pages=246-257; citation_doi=10.1038/nrc3458; citation_id=CR35
citation_journal_title=BMC Cancer; citation_title=Role of the p53/p21 system in the response of human colon carcinoma cells to doxorubicin; citation_author=R Ravizza, MB Gariboldi, L Passarelli, E Monti; citation_volume=4; citation_publication_date=2004; citation_pages=92; citation_doi=10.1186/1471-2407-4-92; citation_id=CR36
citation_journal_title=Oncogene; citation_title=Regulation of the G2/M transition by p53; citation_author=WR Taylor, GR Stark; citation_volume=20; citation_issue=15; citation_publication_date=2001; citation_pages=1803-1815; citation_doi=10.1038/sj.onc.1204252; citation_id=CR37
Williams AB, Schumacher B. p53 in the DNA-Damage-Repair Process. Cold Spring Harb Perspect Med. 2016;6(5).
https://doi.org/10.1101/cshperspect.a026070
.
citation_title=Use of γ-H2AX foci assay on human peripheral blood lymphocytes as sensitive biomarker of exposure; citation_inbook_title=9th symposium of the Croatian radiation protection association: 2013; citation_publication_date=2013; citation_id=CR39; citation_author=M Gerić; citation_author=A Štraser; citation_author=G Gajski; citation_author=J Nunić; citation_author=B Žegura; citation_author=M Filipič; citation_author=V Garaj-Vrhovac
citation_journal_title=Oncogene; citation_title=Regulation of p53 in response to DNA damage; citation_author=ND Lakin, SP Jackson; citation_volume=18; citation_issue=53; citation_publication_date=1999; citation_pages=7644-7655; citation_doi=10.1038/sj.onc.1203015; citation_id=CR40
citation_journal_title=Dev Cell; citation_title=The hippo signaling pathway in development and cancer; citation_author=D Pan; citation_volume=19; citation_issue=4; citation_publication_date=2010; citation_pages=491-505; citation_doi=10.1016/j.devcel.2010.09.011; citation_id=CR41