Skip to main content

Advertisement

SpringerLink
Log in

The BET bromodomain inhibitor i-BET151 impairs ovarian cancer metastasis and improves antitumor immunity

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Ovarian cancer (OC) is a common malignant tumor with a high probability of metastasis. Thus, it is urgently necessary to develop new drugs that inhibit tumor metastasis. Bromodomain and extraterminal (BET) inhibitors targeting bromodomain-containing proteins are currently recognized as novel anticancer agents. Herein, we explored the effects of i-BET151, a BET bromodomain inhibitor, on OC metastasis and on antitumor immunity. Our experiments showed that i-BET151 decreased the viability and induced apoptosis, senescence, and cell cycle arrest of cancer cells. In addition, phosphorylated-Stat3 (Tyr705) amounts OC cell invasion and migration, and expression of matrix metalloproteinases (MMP-9 and MMP-2) decreased. Moreover, tumor metastasis in the abdomen of the OC model was inhibited by i-BET151. Notably, i-BET151-promoted immunogenic cell death (ICD) was confirmed in vivo; it was demonstrated with ICD markers. Furthermore, treatment with i-BET151 promoted infiltration by CD8+ T cells as well as the death of immunogenic tumor cells. In summary, tumor metastasis may be suppressed by i-BET151 via the Stat3 pathway; this approach could be used as a strategy for the treatment of OC.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Aird F, Kandela I, Mantis C, Reproducibility Project: Cancer B (2017) Replication study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Elife 6

  • Bast RC Jr, Hennessy B, Mills GB (2009) The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 9:415–428

    Article  CAS  Google Scholar 

  • Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63

    Article  CAS  Google Scholar 

  • Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904–917

    Article  CAS  Google Scholar 

  • Doherty JA, Peres LC, Wang C, Way GP, Greene CS, Schildkraut JM (2017) Challenges and opportunities in studying the epidemiology of ovarian Cancer subtypes. Curr Epidemiol Rep 4:211–220

    Article  Google Scholar 

  • Doroshow DB, Eder JP, LoRusso PM (2017) BET inhibitors: a novel epigenetic approach. Ann Oncol 28:1776–1787

    Article  CAS  Google Scholar 

  • Enderling H, Hahnfeldt P (2011) Cancer stem cells in solid tumors: is ‘evading apoptosis’ a hallmark of cancer? Prog Biophys Mol Biol 106:391–399

    Article  Google Scholar 

  • Fernald K, Kurokawa M (2013) Evading apoptosis in cancer. Trends Cell Biol 23:620–633

    Article  Google Scholar 

  • Han B, Yao W, Oh YT, Tong JS, Li S, Deng J, Yue P, Khuri FR, Sun SY (2015) The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5. Oncotarget 6:17532–17542

    PubMed  PubMed Central  Google Scholar 

  • Hu J, Zhang L, Chen Q, Lin J, Wang S, Liu R, Zhang W, Miao K, Shou T (2017) Knockdown of CPEB4 expssion suppresses cell migration and invasion via Akt pathway in non-small cell lung cancer. Cell Biol Int

  • Kandela I, Jin HY, Owen K, Reproducibility Project: Cancer B (2015) Registered report: BET bromodomain inhibitionre as a therapeutic strategy to target c-Myc. Elife 4:e07072

    Article  Google Scholar 

  • Klotz DM, Wimberger P (2017) Cells of origin of ovarian cancer: ovarian surface epithelium or fallopian tube? Arch Gynecol Obstet 296:1055–1062

    Article  Google Scholar 

  • Lochrin SE, Price DK, Figg WD (2014) BET bromodomain inhibitors—a novel epigenetic approach in castration-resistant prostate cancer. Cancer Biol Ther 15:1583–1585

    Article  Google Scholar 

  • Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE (2012) Small-molecule inhibition of BRDT for male contraception. Cell 150:673–684

    Article  CAS  Google Scholar 

  • Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, Bao JK (2012) Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 45:487–498

    Article  CAS  Google Scholar 

  • Pan Z, Xie X (2017) BRCA mutations in the manifestation and treatment of ovarian cancer. Oncotarget 8:97657–97670

    PubMed  PubMed Central  Google Scholar 

  • Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, Chanthery YH, Nekritz EA, Zeid R, Gustafson WC, Greninger P, Garnett MJ, McDermott U, Benes CH, Kung AL, Weiss WA, Bradner JE, Stegmaier K (2013) Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov 3:308–323

    Article  CAS  Google Scholar 

  • Qi R, Wang Y, Bruno PM, Xiao H, Yingjie Y, Li T, Lauffer S, Wei W, Chen Q, Kang X, Song H, Yang X, Huang X, Detappe A, Matulonis U, Pepin D, Hemann MT, Birrer MJ, Ghoroghchian PP (2017) Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer. Nat Commun 8:2166

    Article  Google Scholar 

  • Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437

    Article  CAS  Google Scholar 

  • Raja FA, Chopra N, Ledermann JA (2012) Optimal first-line treatment in ovarian cancer. Ann Oncol 23:x118–x127

    Article  Google Scholar 

  • Sharma S, Zuniga F, Rice GE, Perrin LC, Hooper JD, Salomon C (2017) Tumor-derived exosomes in ovarian cancer—liquid biopsies for early detection and real-time monitoring of cancer progression. Oncotarget 8:104687–104703

    PubMed  PubMed Central  Google Scholar 

  • Tong J, Tan S, Nikolovska-Coleska Z, Yu J, Zou F, Zhang L (2017a) FBW7-dependent Mcl-1 degradation mediates the anticancer effect of Hsp90 inhibitors. Mol Cancer Ther 16:1979–1988

    Article  CAS  Google Scholar 

  • Tong J, Tan S, Zou F, Yu J, Zhang L (2017b) FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene 36:787–796

    Article  CAS  Google Scholar 

  • Tong J, Wang P, Tan S, Chen D, Nikolovska-Coleska Z, Zou F, Yu J, Zhang L (2017c) Mcl-1 degradation is required for targeted therapeutics to eradicate Colon cancer cells. Cancer Res 77:2512–2521

    Article  CAS  Google Scholar 

  • Wadhwa E, Nicolaides T (2016) Bromodomain inhibitor review: bromodomain and extra-terminal family protein inhibitors as a potential new therapy in central nervous system tumors. Cureus 8:e620

    PubMed  PubMed Central  Google Scholar 

  • Xie X, Yang M, Ding Y, Chen J (2017) Microbial infection, inflammation and epithelial ovarian cancer. Oncol Lett 14:1911–1919

    Article  CAS  Google Scholar 

  • Xu W, Rush J, Rickett K, Coward JI (2016) Mucinous ovarian cancer: a therapeutic review. Crit Rev Oncol Hematol 102:26–36

    Article  Google Scholar 

  • Zhang XY, Zhang M, Cong Q, Zhang MX, Zhang MY, Lu YY, Xu CJ (2017) Hexokinase 2 confers resistance to cisplatin in ovarian cancer cells by enhancing cisplatin-induced autophagy. Int J Biochem Cell Biol 95:9–16

    Article  Google Scholar 

Download references

Author information

Author notes

  1. Ai Liu and Dianxia Fan contributed equally to this work and should be considered equal first coauthors.

Authors and Affiliations

  1. Obstetrics and Gynecology Department, People’s Hospital of Zoucheng, Jining, Shandong, China

    Ai Liu & Dianxia Fan

  2. Obstetrics and Gynecology Department, Affiliated Hospital of Jining Medical College, 89 Guhuai Rd, Jining, 272000, Shandong, China

    Yanping Wang

Authors
  1. Ai Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dianxia Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yanping Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Statement on the welfare of animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Electronic supplementary material

Figure S1

(a) Colony formation of the indicated cells treated with 5 μM i-BET151 for 2 weeks. Quantification of colony numbers. (b) The indicated cell lines were treated with 5 μM i-BET151 for 24 h. Cleaved caspase 3 was analyzed by Western blotting. (c) The indicated cell lines were treated with 5 μM i-BET151 for 24 h. Cell cycle was analyzed by flow cytometry. (PNG 234 kb)

High resolution image (TIF 5707 kb)

Figure S2

(a-c) ID8 cells were treated with i-BET151. Migration was analyzed by the Transwell assay. Scale bars: 20 μm. (d-f) ID8 cells were treated with i-BET151. Invasion was analyzed by the Transwell assay. Scale bars: 20 μm. (PNG 839 kb)

High resolution image (TIF 6685 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, A., Fan, D. & Wang, Y. The BET bromodomain inhibitor i-BET151 impairs ovarian cancer metastasis and improves antitumor immunity. Cell Tissue Res 374, 577–585 (2018). https://doi.org/10.1007/s00441-018-2906-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-018-2906-y

Keywords

Search

Navigation