Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
June-2016 Volume 48 Issue 6

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
June-2016 Volume 48 Issue 6

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231

  • Authors:
    • Anna De Blasio
    • Riccardo Di Fiore
    • Marco Morreale
    • Daniela Carlisi
    • Rosa Drago-Ferrante
    • Mauro Montalbano
    • Christian Scerri
    • Giovanni Tesoriere
    • Renza Vento
  • View Affiliations / Copyright

    Affiliations: Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Polyclinic, Palermo, Italy, Laboratory of Biochemistry, Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Polyclinic, Palermo, Italy, Department of Physiology and Biochemistry, University of Malta, Msida, Malta, Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA
  • Pages: 2339-2348
    |
    Published online on: April 6, 2016
       https://doi.org/10.3892/ijo.2016.3474
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Triple-negative breast cancer (TNBC) is a clinically aggressive form of breast cancer that is unresponsive to endocrine agents or trastuzumab. TNBC accounts for ~10-20% of all breast cancer cases and represents the form with the poorest prognosis. Patients with TNBC are at higher risk of early recurrence, mainly in the lungs, brain and soft tissue, therefore, there is an urgent need for new therapies. The present study was carried out in MDA-MB-231 cells, where we assessed the role of caspase-8 (casp-8), a critical effector of death receptors, also involved in non‑apoptotic functions. Analysis of casp-8 mRNA and protein levels indicated that they were up-regulated with respect to the normal human mammalian epithelial cells. We demonstrated that silencing of casp-8 by small interfering-RNA, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypo-phosphorylated/active form of pRb levels. Surprisingly, casp-8-knockdown, also potently increased both the migratory and metastatic capacity of MDA-MB‑231 cells, as shown by both wound healing and Matrigel assay, and by the expression of a number of related-genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2. Among these, KLF4, a transcriptional factor with a dual role (activator and repressor), seemed to play critical roles. We suggest that in MDA-MB‑231 cells, the endogenous expression of casp-8 might keep the cells perpetually cycling through downregulation of KLF4, the subsequent lowering of p21 and p27, and the inactivation by hyperphosphorylation of pRb. Simultaneously, by lowering the expression of some migratory and invasive genes, casp-8 might restrain the metastatic ability of the cells. Overall, our findings showed that, in MDA-MB-231 cells, casp-8 might play some unusual roles which should be better explored, in order to understand whether it might be identified as a molecular therapeutic target.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Kim HS, Lee JW, Soung YH, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Jeong SW, et al: Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology. 125:708–715. 2003. View Article : Google Scholar : PubMed/NCBI

2 

Torres VA, Mielgo A, Barbero S, Hsiao R, Wilkins JA and Stupack DG: Rab5 mediates caspase-8-promoted cell motility and metastasis. Mol Biol Cell. 21:369–376. 2010. View Article : Google Scholar :

3 

Stupack DG, Teitz T, Potter MD, Mikolon D, Houghton PJ, Kidd VJ, Lahti JM and Cheresh DA: Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature. 439:95–99. 2006. View Article : Google Scholar : PubMed/NCBI

4 

Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM and Kidd VJ: Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med. 6:529–535. 2000. View Article : Google Scholar : PubMed/NCBI

5 

Pingoud-Meier C, Lang D, Janss AJ, Rorke LB, Phillips PC, Shalaby T and Grotzer MA: Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma. Clin Cancer Res. 9:6401–6409. 2003.PubMed/NCBI

6 

Skiriute D, Vaitkiene P, Saferis V, Asmoniene V, Skauminas K, Deltuva VP and Tamasauskas A: MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma. BMC Cancer. 12:2182012. View Article : Google Scholar : PubMed/NCBI

7 

Hopkins-Donaldson S, Ziegler A, Kurtz S, Bigosch C, Kandioler D, Ludwig C, Zangemeister-Wittke U and Stahel R: Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ. 10:356–364. 2003. View Article : Google Scholar : PubMed/NCBI

8 

Soung YH, Lee JW, Kim SY, Sung YJ, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ and Lee SH: Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas. Oncogene. 24:141–147. 2005. View Article : Google Scholar

9 

Soung YH, Lee JW, Kim SY, Jang J, Park YG, Park WS, Nam SW, Lee JY, Yoo NJ and Lee SH: Caspase-8 gene is inactivated by somatic mutations in gastric carcinomas. Cancer Res. 65:815–821. 2005.PubMed/NCBI

10 

American Cancer Society. Surveillance and Heath Services Research. 2015, http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2015/.

11 

Zhang J, Wang Y, Yin Q, Zhang W, Zhang T and Niu Y: An associated classification of triple negative breast cancer: The risk of relapse and the response to chemotherapy. Int J Clin Exp Pathol. 6:1380–1391. 2013.PubMed/NCBI

12 

Bauer KR, Brown M, Cress RD, Parise CA and Caggiano V: Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 109:1721–1728. 2007. View Article : Google Scholar : PubMed/NCBI

13 

Bayraktar S and Glück S: Molecularly targeted therapies for metastatic triple-negative breast cancer. Breast Cancer Res Treat. 138:21–35. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Yagata H, Kajiura Y and Yamauchi H: Current strategy for triple-negative breast cancer: Appropriate combination of surgery, radiation, and chemotherapy. Breast Cancer. 18:165–173. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Pogoda K, Niwińska A, Murawska M and Pieńkowski T: Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 30:3882013. View Article : Google Scholar : PubMed/NCBI

16 

D'Anneo A, Carlisi D, Lauricella M, Puleio R, Martinez R, Di Bella S, Di Marco P, Emanuele S, Di Fiore R, Guercio A, et al: Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasis in a xenograft model of breast cancer. Cell Death Dis. 4:e8912013. View Article : Google Scholar : PubMed/NCBI

17 

Carlisi D, Lauricella M, D'Anneo A, Emanuele S, Angileri L, Di Fazio P, Santulli A, Vento R and Tesoriere G: The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation. Eur J Cancer. 45:2425–2438. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Lauricella M, Ciraolo A, Carlisi D, Vento R and Tesoriere G: SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells. Biochimie. 94:287–299. 2012. View Article : Google Scholar

19 

Carlisi D, Lauricella M, D'Anneo A, Buttitta G, Emanuele S, di Fiore R, Martinez R, Rolfo C, Vento R and Tesoriere G: The synergistic effect of SAHA and parthenolide in MDA-MB231 breast cancer cells. J Cell Physiol. 230:1276–1289. 2015. View Article : Google Scholar

20 

Di Fiore R, Marcatti M, Drago-Ferrante R, D'Anneo A, Giuliano M, Carlisi D, De Blasio A, Querques F, Pastore L, Tesoriere G, et al: Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells. Bone. 60:198–212. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Di Fiore R, Drago-Ferrante R, Pentimalli F, Di Marzo D, Forte IM, D'Anneo A, Carlisi D, De Blasio A, Giuliano M, Tesoriere G, et al: MicroRNA-29b-1 impairs in vitro cell proliferation, self-renewal and chemoresistance of human osteosarcoma 3AB-OS cancer stem cells. Int J Oncol. 45:2013–2023. 2014.PubMed/NCBI

22 

Gorter A, Zijlmans HJ, van Gent H, Trimbos JB, Fleuren GJ and Jordanova ES: Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer. Mod Pathol. 23:1605–1615. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Ricciardelli C, Sakko AJ, Ween MP, Russell DL and Horsfall DJ: The biological role and regulation of versican levels in cancer. Cancer Metastasis Rev. 28:233–245. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Jäger R and Zwacka RM: The enigmatic roles of caspases in tumor development. Cancers (Basel). 2:1952–1979. 2010. View Article : Google Scholar

25 

Stupack DG: Caspase-8 as a therapeutic target in cancer. Cancer Lett. 332:133–140. 2013. View Article : Google Scholar

26 

Ell B and Kang Y: Transcriptional control of cancer metastasis. Trends Cell Biol. 23:603–611. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Weigelt B, Peterse JL and van ‘t Veer LJ: Breast cancer metastasis: Markers and models. Nat Rev Cancer. 5:591–602. 2005. View Article : Google Scholar : PubMed/NCBI

28 

Nakopoulou L, Tsirmpa I, Alexandrou P, Louvrou A, Ampela C, Markaki S and Davaris PS: MMP-2 protein in invasive breast cancer and the impact of MMP-2/TIMP-2 phenotype on overall survival. Breast Cancer Res Treat. 77:145–155. 2003. View Article : Google Scholar : PubMed/NCBI

29 

Tiwari N, Meyer-Schaller N, Arnold P, Antoniadis H, Pachkov M, van Nimwegen E and Christofori G: Klf4 is a transcriptional regulator of genes critical for EMT, including Jnk1 (Mapk8). PLoS One. 8:e573292013. View Article : Google Scholar : PubMed/NCBI

30 

Shi Y and Ai W: Function of KLF4 in stem cell biology. Biochemistry, Genetics and Molecular Biology ‘Pluripotent Stem Cells’. Bhartiya D and Lenka N: InTech; 2013

31 

Rowland BD, Bernards R and Peeper DS: The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat Cell Biol. 7:1074–1082. 2005. View Article : Google Scholar : PubMed/NCBI

32 

Wei D, Kanai M, Jia Z, Le X and Xie K: Kruppel-like factor 4 induces p27Kip1 expression in and suppresses the growth and metastasis of human pancreatic cancer cells. Cancer Res. 68:4631–4639. 2008. View Article : Google Scholar : PubMed/NCBI

33 

Nagata T, Shimada Y, Sekine S, Hori R, Matsui K, Okumura T, Sawada S, Fukuoka J and Tsukada K: Prognostic significance of NANOG and KLF4 for breast cancer. Breast Cancer. 21:96–101. 2014. View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
De Blasio A, Di Fiore R, Morreale M, Carlisi D, Drago-Ferrante R, Montalbano M, Scerri C, Tesoriere G and Vento R: Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231. Int J Oncol 48: 2339-2348, 2016.
APA
De Blasio, A., Di Fiore, R., Morreale, M., Carlisi, D., Drago-Ferrante, R., Montalbano, M. ... Vento, R. (2016). Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231. International Journal of Oncology, 48, 2339-2348. https://doi.org/10.3892/ijo.2016.3474
MLA
De Blasio, A., Di Fiore, R., Morreale, M., Carlisi, D., Drago-Ferrante, R., Montalbano, M., Scerri, C., Tesoriere, G., Vento, R."Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231". International Journal of Oncology 48.6 (2016): 2339-2348.
Chicago
De Blasio, A., Di Fiore, R., Morreale, M., Carlisi, D., Drago-Ferrante, R., Montalbano, M., Scerri, C., Tesoriere, G., Vento, R."Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231". International Journal of Oncology 48, no. 6 (2016): 2339-2348. https://doi.org/10.3892/ijo.2016.3474
Copy and paste a formatted citation
x
Spandidos Publications style
De Blasio A, Di Fiore R, Morreale M, Carlisi D, Drago-Ferrante R, Montalbano M, Scerri C, Tesoriere G and Vento R: Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231. Int J Oncol 48: 2339-2348, 2016.
APA
De Blasio, A., Di Fiore, R., Morreale, M., Carlisi, D., Drago-Ferrante, R., Montalbano, M. ... Vento, R. (2016). Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231. International Journal of Oncology, 48, 2339-2348. https://doi.org/10.3892/ijo.2016.3474
MLA
De Blasio, A., Di Fiore, R., Morreale, M., Carlisi, D., Drago-Ferrante, R., Montalbano, M., Scerri, C., Tesoriere, G., Vento, R."Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231". International Journal of Oncology 48.6 (2016): 2339-2348.
Chicago
De Blasio, A., Di Fiore, R., Morreale, M., Carlisi, D., Drago-Ferrante, R., Montalbano, M., Scerri, C., Tesoriere, G., Vento, R."Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231". International Journal of Oncology 48, no. 6 (2016): 2339-2348. https://doi.org/10.3892/ijo.2016.3474
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team