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
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
January-2021 Volume 45 Issue 1

Full Size Image

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
January-2021 Volume 45 Issue 1

Full Size Image

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

  • Supplementary Files
    • Supplementary_Data.pdf
Article

Zoledronic acid impairs oral cancer stem cells by reducing CCL3

  • Authors:
    • Sung Hee Lee
    • Nicole Rigas
    • Charlotte Ellen Martin
    • Anthony Nguyen
    • Mo K. Kang
    • No‑Hee Park
    • Reuben H. Kim
    • Ki‑Hyuk Shin
  • View Affiliations / Copyright

    Affiliations: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA 90095, USA
  • Pages: 291-298
    |
    Published online on: November 5, 2020
       https://doi.org/10.3892/or.2020.7835
  • 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

Cancer stem‑like cells (CSCs; also referred to as tumor‑initiating cells) play crucial roles in tumor progression and aggressiveness. Recent studies have demonstrated the antitumor activity of zoledronic acid (ZA), a third‑generation bisphosphonate, in various types of human cancer. However, its effect on oral CSCs and the underlying mechanism remain obscure. The present study demonstrated that ZA suppresses the growth and stemness properties of oral/oropharyngeal squamous cell carcinoma (OSCC) cells. ZA inhibited the malignant characteristics of OSCC cells, such as anchorage‑independent growth and epithelial thickening in organotypic raft cultures. Moreover, ZA treatment resulted in suppression of self‑renewal capacity, a key feature of CSCs. ZA also inhibited important CSC properties, such as migration and chemo‑radioresistance. Mechanistically, ZA exposure significantly decreased chemokine (C‑C motif) ligand 3 (CCL3) expression in OSCC cells. It was further demonstrated that CCL3 signaling via its receptor is crucial for supporting the CSC phenotype in OSCC cells. Moreover, an antagonist of the CCL3 receptor reversed the effect of CCL3 on CSC properties, and exogenous CCL3 rescued the suppressaed CSC phenotype in ZA‑treated OSCC cells. These results demonstrated that ZA suppresses the CSC phenotype in OSCC cells by reducing CCL3 expression, suggesting that ZA may be an effective therapeutic agent for oral cancer by targeting CSCs.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Warnakulasuriya S: Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 45:309–316. 2009. View Article : Google Scholar

2 

Shin KH and Kim RH: An updated review of oral cancer stem cells and their stemness regulation. Crit Rev Oncog. 23:189–200. 2018. View Article : Google Scholar

3 

O'Brien CA, Kreso A and Jamieson CH: Cancer stem cells and self-renewal. Clin Cancer Res. 16:3113–3120. 2010. View Article : Google Scholar

4 

Lee CR, Lee SH, Rigas NK, Kim RH, Kang MK, Park NH and Shin KH: Elevated expression of JMJD6 is associated with oral carcinogenesis and maintains cancer stemness properties. Carcinogenesis. 37:119–128. 2016. View Article : Google Scholar

5 

Lee SH, Lee CR, Rigas NK, Kim RH, Kang MK, Park NH and Shin KH: Human papillomavirus 16 (HPV16) enhances tumor growth and cancer stemness of HPV-negative oral/oropharyngeal squamous cell carcinoma cells via miR-181 regulation. Papillomavirus Res. 1:116–125. 2015. View Article : Google Scholar

6 

Lee SH, Rigas NK, Lee CR, Bang A, Srikanth S, Gwack Y, Kang MK, Kim RH, Park NH and Shin KH: Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma. Oncotarget. 7:43239–43255. 2016. View Article : Google Scholar

7 

Tamura T, Shomori K, Nakabayashi M, Fujii N, Ryoke K and Ito H: Zoledronic acid, a third-generation bisphosphonate, inhibits cellular growth and induces apoptosis in oral carcinoma cell lines. Oncol Rep. 25:1139–1143. 2011. View Article : Google Scholar

8 

Martin CK, Werbeck JL, Thudi NK, Lanigan LG, Wolfe TD, Toribio RE and Rosol TJ: Zoledronic acid reduces bone loss and tumor growth in an orthotopic xenograft model of osteolytic oral squamous cell carcinoma. Cancer Res. 70:8607–8616. 2010. View Article : Google Scholar

9 

Okamoto S, Kawamura K, Li Q, Yamanaka M, Yang S, Fukamachi T, Tada Y, Tatsumi K, Shimada H, Hiroshima K, et al: Zoledronic acid produces antitumor effects on mesothelioma through apoptosis and S-phase arrest in p53-independent and Ras prenylation-independent manners. J Thorac Oncol. 7:873–882. 2012. View Article : Google Scholar

10 

Corey E, Brown LG, Quinn JE, Poot M, Roudier MP, Higano CS and Vessella RL: Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res. 9:295–306. 2003.

11 

Jiang P, Zhang P, Mukthavaram R, Nomura N, Pingle SC, Teng D, Chien S, Guo F and Kesari S: Anti-cancer effects of nitrogen-containing bisphosphonates on human cancer cells. Oncotarget. 7:57932–57942. 2016. View Article : Google Scholar

12 

Sewing L, Steinberg F, Schmidt H and Göke R: The bisphosphonate zoledronic acid inhibits the growth of HCT-116 colon carcinoma cells and induces tumor cell apoptosis. Apoptosis. 13:782–789. 2008. View Article : Google Scholar

13 

Li Y, Du Y, Sun T, Xue H, Jin Z and Tian J: PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse model. BMC Cancer. 18:6692018. View Article : Google Scholar

14 

Vitellius C, Fizanne L, Menager-Tabourel E, Nader J, Baize N, Laly M, Lermite E, Bertrais S and Caroli-Bosc FX: The combination of everolimus and zoledronic acid increase the efficacy of gemcitabine in a mouse model of pancreatic adenocarcinoma. Oncotarget. 9:28069–28082. 2018. View Article : Google Scholar

15 

Barrett-Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, Timmins H, Wheatley D, Grieve R, Griffiths G and Murray N: Oral ibandronic acid vs. intravenous zoledronic acid in treatment of bone metastases from breast cancer: A randomised, open label, non-inferiority phase 3 trial. Lancet Oncol. 15:114–122. 2014. View Article : Google Scholar

16 

Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, Keane M, Gil M, Burkinshaw R, Grieve R, et al: Adjuvant zoledronic acid in patients with early breast cancer: Final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol. 15:997–1006. 2014. View Article : Google Scholar

17 

Lee SH, Hong HS, Liu ZX, Kim RH, Kang MK, Park NH and Shin KH: TNFα enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells. Biochem Biophys Res Commun. 424:58–64. 2012. View Article : Google Scholar

18 

Shin KH, Bae SD, Hong HS, Kim RH, Kang MK and Park NH: miR-181a shows tumor suppressive effect against oral squamous cell carcinoma cells by downregulating K-ras. Biochem Biophys Res Commun. 404:896–902. 2011. View Article : Google Scholar

19 

Yanamoto S, Kawasaki G, Yamada S, Yoshitomi I, Kawano T, Yonezawa H, Rokutanda S, Naruse T and Umeda M: Isolation and characterization of cancer stem-like side population cells in human oral cancer cells. Oral Oncol. 47:855–860. 2011. View Article : Google Scholar

20 

Zhang P, Zhang Y, Mao L, Zhang Z and Chen W: Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes. Cancer Lett. 277:227–234. 2009. View Article : Google Scholar

21 

Baba T, Naka K, Morishita S, Komatsu N, Hirao A and Mukaida N: MIP-1α/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia. J Exp Med. 210:2661–2673. 2013. View Article : Google Scholar

22 

Blanpain C, Buser R, Power CA, Edgerton M, Buchanan C, Mack M, Simmons G, Clapham PR, Parmentier M and Proudfoot AE: A chimeric MIP-1 alpha/RANTES protein demonstrates the use of different regions of the RANTES protein to bind and activate its receptors. J Leukocyte Biol. 69:977–985. 2001.

23 

Schech AJ, Kazi AA, Gilani RA and Brodie AH: Zoledronic acid reverses the epithelial-mesenchymal transition and inhibits self-renewal of breast cancer cells through inactivation of NF-κB. Mol Cancer Ther. 12:1356–1366. 2013. View Article : Google Scholar

24 

Buhler H, Hoberg C, Fakhrian K and Adamietz IA: Zoledronic acid inhibits the motility of cancer stem-like cells from the human breast cancer cell line MDA-MB 231. In Vivo. 30:761–768. 2016. View Article : Google Scholar

25 

Rouhrazi H, Turgan N and Oktem G: Zoledronic acid overcomes chemoresistance by sensitizing cancer stem cells to apoptosis. Biotech Histochem. 93:77–88. 2018. View Article : Google Scholar

26 

Kijima T, Koga F, Fujii Y, Yoshida S, Tatokoro M and Kihara K: Zoledronic acid sensitizes renal cell carcinoma cells to radiation by downregulating STAT1. PLoS One. 8:e646152013. View Article : Google Scholar

27 

Silva TA, Ribeiro FL, Oliveira-Neto HH, Watanabe S, Alencar Rde C, Fukada SY, Cunha FQ, Leles CR, Mendonça EF and Batista AC: Dual role of CCL3/CCR1 in oral squamous cell carcinoma: Implications in tumor metastasis and local host defense. Oncol Rep. 18:1107–1113. 2007.

28 

da Silva JM, Moreira Dos Santos TP, Sobral LM, Queiroz-Junior CM, Rachid MA, Proudfoot AEI, Garlet GP, Batista AC, Teixeira MM, Leopoldino AM, et al: Relevance of CCL3/CCR5 axis in oral carcinogenesis. Oncotarget. 8:51024–51036. 2017. View Article : Google Scholar

29 

Hsu CJ, Wu MH, Chen CY, Tsai CH, Hsu HC and Tang CH: AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma. Cell Commun Signal. 11:682013. View Article : Google Scholar

30 

Liao YY, Tsai HC, Chou PY, Wang SW, Chen HT, Lin YM, Chiang IP, Chang TM, Hsu SK, Chou MC, et al: CCL3 promotes angiogenesis by dysregulation of miR-374b/ VEGF-A axis in human osteosarcoma cells. Oncotarget. 7:4310–4325. 2016. View Article : Google Scholar

31 

Kim JH, Kim WS, Hong JY, Ryu KJ, Kim SJ and Park C: Epstein-Barr virus EBNA2 directs doxorubicin resistance of B cell lymphoma through CCL3 and CCL4-mediated activation of NF-kappaB and Btk. Oncotarget. 8:5361–5370. 2017. View Article : Google Scholar

32 

Jin J, Colin P, Staropoli I, Lima-Fernandes E, Ferret C, Demir A, Rogée S, Hartley O, Randriamampita C, Scott MG, et al: Targeting spare CC chemokine receptor 5 (CCR5) as a principle to inhibit HIV-1 entry. J Biol Chem. 289:19042–19052. 2014. View Article : Google Scholar

33 

Jiao X, Velasco-Velázquez MA, Wang M, Li Z, Rui H, Peck AR, Korkola JE, Chen X, Xu S, DuHadaway JB, et al: CCR5 governs DNA damage repair and breast cancer Stem cell expansion. Cancer Res. 78:1657–1671. 2018. View Article : Google Scholar

34 

Mencarelli A, Graziosi L, Renga B, Cipriani S, D'Amore C, Francisci D, Bruno A, Baldelli F, Donini A and Fiorucci S: CCR5 antagonism by maraviroc reduces the potential for gastric cancer cell dissemination. Transl Oncol. 6:784–793. 2013. View Article : Google Scholar

35 

Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP and Pestell RG: CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 72:3839–3850. 2012. View Article : Google Scholar

36 

Maehara O, Suda G, Natsuizaka M, Ohnishi S, Komatsu Y, Sato F, Nakai M, Sho T, Morikawa K, Ogawa K, et al: Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma. Carcinogenesis. 38:1073–1083. 2017. View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Lee SH, Rigas N, Martin CE, Nguyen A, Kang MK, Park NH, Kim RH and Shin KH: Zoledronic acid impairs oral cancer stem cells by reducing CCL3. Oncol Rep 45: 291-298, 2021.
APA
Lee, S.H., Rigas, N., Martin, C.E., Nguyen, A., Kang, M.K., Park, N. ... Shin, K. (2021). Zoledronic acid impairs oral cancer stem cells by reducing CCL3. Oncology Reports, 45, 291-298. https://doi.org/10.3892/or.2020.7835
MLA
Lee, S. H., Rigas, N., Martin, C. E., Nguyen, A., Kang, M. K., Park, N., Kim, R. H., Shin, K."Zoledronic acid impairs oral cancer stem cells by reducing CCL3". Oncology Reports 45.1 (2021): 291-298.
Chicago
Lee, S. H., Rigas, N., Martin, C. E., Nguyen, A., Kang, M. K., Park, N., Kim, R. H., Shin, K."Zoledronic acid impairs oral cancer stem cells by reducing CCL3". Oncology Reports 45, no. 1 (2021): 291-298. https://doi.org/10.3892/or.2020.7835
Copy and paste a formatted citation
x
Spandidos Publications style
Lee SH, Rigas N, Martin CE, Nguyen A, Kang MK, Park NH, Kim RH and Shin KH: Zoledronic acid impairs oral cancer stem cells by reducing CCL3. Oncol Rep 45: 291-298, 2021.
APA
Lee, S.H., Rigas, N., Martin, C.E., Nguyen, A., Kang, M.K., Park, N. ... Shin, K. (2021). Zoledronic acid impairs oral cancer stem cells by reducing CCL3. Oncology Reports, 45, 291-298. https://doi.org/10.3892/or.2020.7835
MLA
Lee, S. H., Rigas, N., Martin, C. E., Nguyen, A., Kang, M. K., Park, N., Kim, R. H., Shin, K."Zoledronic acid impairs oral cancer stem cells by reducing CCL3". Oncology Reports 45.1 (2021): 291-298.
Chicago
Lee, S. H., Rigas, N., Martin, C. E., Nguyen, A., Kang, M. K., Park, N., Kim, R. H., Shin, K."Zoledronic acid impairs oral cancer stem cells by reducing CCL3". Oncology Reports 45, no. 1 (2021): 291-298. https://doi.org/10.3892/or.2020.7835
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