Skip to main content
SpringerLink
Log in

Smenospongidine suppresses the proliferation of multiple myeloma cells by promoting CCAAT/enhancer-binding protein homologous protein-mediated β-catenin degradation

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Abnormal up-regulation of β-catenin expression is associated with the development and progression of multiple myeloma and is thus a potential therapeutic target. Here, we screened cell-based natural compounds and identified smenospongidine, a metabolite isolated from a marine sponge, as an antagonist of the Wnt/β-catenin signaling pathway. Smenospongidine promoted the degradation of intracellular β-catenin that accumulated via Wnt3a or 6-bromoindirubin-3′-oxime, an inhibitor of glycogen synthase kinase-3β. Consistently, smenospongidine down-regulated β-catenin expression and repressed the levels of β-catenin/T cell factor-dependent genes such as axin2, c-myc, and cyclin D1 in RPMI-8226 multiple myeloma cells. Smenospongidine suppressed proliferation and significantly induced apoptosis in RPMI-8266 cells. In addition, smenospongidine-induced β-catenin degradation was mediated by up-regulating CCAAT/enhancer-binding protein homologous protein (CHOP). These findings indicate that smenospongidine exerts its anti-proliferative activity by blocking the Wnt/β-catenin signaling pathway and may be a potential chemotherapeutic agent against multiple myeloma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aberle H, Bauer A, Stappert J, Kispert A, Kemler R (1997) β-Catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16:3797–3804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aoki S, Kong D, Matsui K, Rachmat R, Kobayashi M (2004) Sesquiterpene aminoquinones, from a marine sponge, induce erythroid differentiation in human chronic myelogenous leukemia, K562 cells. Chem Pharm Bull 52:935–937

    Article  CAS  PubMed  Google Scholar 

  • Ashihara E, Kawata E, Nakagawa Y, Shimazaski C, Kuroda J, Taniguchi K, Uchiyama H, Tanaka R, Yokota A, Takeuchi M, Kamitsuji Y, Inaba T, Taniwaki M, Kimura S, Maekawa T (2009) β-Catenin small interfering RNA successfully suppressed progression of multiple myeloma in a mouse model. Clin Cancer Res 15:2731–2738

    Article  CAS  PubMed  Google Scholar 

  • Bharti AC, Donato N, Singh S, Aggarwal BB (2003) Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkBα kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 101:1053–1062

    Article  CAS  PubMed  Google Scholar 

  • Cho M, Gwak J, Park S, Won J, Kim DE, Yea SS, Cha IJ, Kim TK, Shin JG, Oh S (2005) Diclofenac attenuates Wnt/beta-catenin signaling in colon cancer cells by activation of NF-Κb. FEBS Lett 579:4213–4218

    Article  CAS  PubMed  Google Scholar 

  • Derksen PW, Tjin E, Meijer HP, Klok MD, MacGillavry HD, van Oers MH, Lokhorst HM, Bloem AC, Clevers H, Nusse R, van der Neut R, Spaargaren M, Pals ST (2004) Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc Natl Acad Sci USA 101:6122–6127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dignam JD, Lebovitz RM, Roeder RG (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11:1475–1489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta SC, Patchva S, Aggarwal BB (2013) Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J 15:195–218

    Article  CAS  PubMed  Google Scholar 

  • Gwak J, Oh J, Cho M, Bae SK, Song IS, Liu KH, Jeong Y, Kim DE, Chung YH, Oh S (2011) Galangin suppresses the proliferation of β-catenin response transcription-positive cancer cells by promoting adenomatous polyposis coli/Axin/glycogen synthase kinase-3β-independent β-catenin degradation. Mol Pharmacol 79:1014–1022

    Article  CAS  PubMed  Google Scholar 

  • Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P (1998) Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3-β. Curr Biol 8:573–581

    Article  CAS  PubMed  Google Scholar 

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512

    Article  CAS  PubMed  Google Scholar 

  • Horndasch M, Lienkamp S, Springer E, Schmitt A, Pavenstädt H, Walz G, Gloy J (2006) The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals. Oncogene 25:3397–3407

    Article  CAS  PubMed  Google Scholar 

  • Hwang IH, Oh J, Zhou W, Park S, Kim JH, Chittiboyina AG, Ferreira D, Song GY, Oh S, Na M, Hamann MT (2015) Cytotoxic activity of rearranged drimane meroterpenoids against colon cancer cells via down-regulation of β-catenin expression. J Nat Prod 78:453–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F (2002) Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22:1172–1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kondracki ML, Guyot M (1989) Biologically active quinone and hydroquinone sesquiterpenoids from the sponge Smenospongia sp. Tetrahedron 45:1995–2004

    Article  CAS  Google Scholar 

  • Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X (2002) Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108:837–847

    Article  CAS  PubMed  Google Scholar 

  • MacDonald BT, Tamai K, He X (2009) Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell 12:9–26

    Article  Google Scholar 

  • Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Knockaert M, Leost M, Ryan XP, Vonica CA, Brivanlou A, Dajani R, Crovace C, Tarricone C, Musacchio A, Roe SM, Pearl L, Greengard P (2003) GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chem Biol 10:1255–1266

    Article  CAS  PubMed  Google Scholar 

  • Miller JR (2002) The Wnts. Genome Biol 3: REVIEWS3001

  • Oda T, Wang W, Ukai K, Nakazawa T, Mochizuki M (2007) A sesquiterpene quinone, 5-epi-smenospongine, promotes TNF-α production in LPS-stimulated RAW 264.7 cells. Mar Drugs 5:151–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389

    Article  CAS  PubMed  Google Scholar 

  • Park S, Gwak J, Cho M, Song T, Won J, Kim DE, Shin JG, Oh S (2006) Hexachlorophene inhibits Wnt/β-catenin pathway by promoting Siah-mediated beta-catenin degradation. Mol Pharmacol 70:960–966

    Article  CAS  PubMed  Google Scholar 

  • Park S, Yun E, Hwang IH, Yoon S, Kim DE, Kim JS, Na M, Song GY, Oh S (2014) Ilimaquinone and ethylsmenoquinone, marine sponge metabolites, suppress the proliferation of multiple myeloma cells by down-regulating the level of β-catenin. Mar Drugs 12:3231–3244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337–1349

    Article  CAS  PubMed  Google Scholar 

  • Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC (2009) Multiple myeloma. Lancet 374:324–339

    Article  PubMed  Google Scholar 

  • Rodriguez J, Quinoa E, Riguera R, Peters BM, Abrell LM, Crews P (1992) The structures and stereochemistry of cytotoxic sesquiterpene quinones from Dactylospongia elegans. Tetrahedron 48:6667–6680

    Article  CAS  Google Scholar 

  • Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P (1996) Binding of GSK3beta to the APC-β-catenin complex and regulation of complex assembly. Science 272:1023–1026

    Article  CAS  PubMed  Google Scholar 

  • Ryu MJ, Cho M, Song JY, Yun YS, Choi IW, Kim DE, Park BS, Oh S (2008) Natural derivatives of curcumin attenuate the Wnt/β-catenin pathway through down-regulation of the transcriptional coactivator p300. Biochem Biophys Res Commun 377:1304–1308

    Article  CAS  PubMed  Google Scholar 

  • Sukhdeo K, Mani M, Zhang Y, Dutta J, Yasui H, Rooney MD, Carrasco DE, Zheng M, He H, Tai YT, Mitsiades C, Anderson KC, Carrasco DR (2007) Targeting the β-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci USA 104:7516–7521

    Article  PubMed  PubMed Central  Google Scholar 

  • Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13:184–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tetsu O, McCormick F (1999) β-Catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426

    Article  CAS  PubMed  Google Scholar 

  • Wodarz A, Nusse R (1998) Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 14:59–88

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi H, Wang HG (2004) CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 279:45495–45502

    Article  CAS  PubMed  Google Scholar 

  • Yao H, Ashihara E, Strovel JW, Nakagawa Y, Kuroda J, Nagao R, Tanaka R, Yokota A, Takeuchi M, Hayashi Y, Shimazaki C, Taniwaki M, Strand K, Padia J, Hirai H, Kimura S, Maekawa T (2011) AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model. Blood Cancer J 1:e43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledegements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Korean government (NRF-2015R1A2A2A01004599, NRF-2014R1A2A2A01006793) and the High Value-added Food Technology Development Program (114030-3) funded by the Ministry of Agriculture, Food and Rural Affairs.

Author information

Authors and Affiliations

  1. Department of Bio and Fermentation Convergence Technology, BK21 PLUS program, Kookmin University, Seoul, 02707, Republic of Korea

    Seoyoung Park, Jiseon Kim & Sangtaek Oh

  2. College of Pharmacy, Woosuk University, Wanju, Jeonbuk, 55338, Republic of Korea

    In Hyun Hwang

  3. BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, 609-735, Republic of Korea

    Young-Hwa Chung

  4. College of Pharmacy, Chungnam National University, Daejeon, 34134, Republic of Korea

    Gyu-Young Song & MinKyun Na

  5. Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul, 02707, Republic of Korea

    Sangtaek Oh

Authors
  1. Seoyoung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. In Hyun Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiseon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Young-Hwa Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gyu-Young Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. MinKyun Na
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sangtaek Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to MinKyun Na or Sangtaek Oh.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 63 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, S., Hwang, I.H., Kim, J. et al. Smenospongidine suppresses the proliferation of multiple myeloma cells by promoting CCAAT/enhancer-binding protein homologous protein-mediated β-catenin degradation. Arch. Pharm. Res. 40, 592–600 (2017). https://doi.org/10.1007/s12272-017-0906-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-017-0906-1

Keywords

Search

Navigation