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
February-2016 Volume 35 Issue 2

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
February-2016 Volume 35 Issue 2

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
Article

Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15

  • Authors:
    • Zhiyong Weng
    • Hongguo Gao
    • Jiehua Hu
    • Yonggang Fan
    • Hongyan Wang
    • Lihua Li
  • View Affiliations / Copyright

    Affiliations: Department of Cell Biology, Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China, Department of Clinical Laboratory, Daqing Oilfield General Hospital, Daqing 163001, P.R. China, Educational Technologies and Simulation Training Centre, Naval University of Engineering Tianjin Campus, Tianjin 300450, P.R. China
  • Pages: 833-840
    |
    Published online on: November 26, 2015
       https://doi.org/10.3892/or.2015.4461
  • 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

We investigated the effects of isoalantolactone on cell growth inhibition and underlying cell death mechanisms in SKOV3 human ovarian cancer cells. The effects of isoalantolactone on cell proliferation and cell cycle were examined by EdU incorporation assay and DNA content assay. Western blotting was performed to determine the protein expression effects of isoalantolactone on cell cycle‑related proteins, autophagic regulators and PEA‑15. Autophagic vacuoles were observed by acridine orange staining. PEA‑15 knockdown by siRNA was used to confirm that PEA‑15 was involved in isoalantolactone‑induced autophagy of SKOV3 cells. Isoalantolactone inhibited the viability and proliferation of SKOV3 cells in a dose‑ and time‑dependent fashion. Isoalantolactone induced cell cycle arrest at G2/M phase and decreased the expression of cell cycle‑related proteins cyclin B1 and CDK1 in SKOV3 cells. Accordingly, isoalantolactone also induced SKOV3 cell autophagy via accumulation of autophagic vacuoles in the cytoplasm, increased Beclin1 protein expression, and increased LC3 cleavage. Furthermore, we observed that isoalantolactone‑induced autophagy was through increased PEA‑15 expression and the phosphorylation of ERK, whereas less change was observed to autophagy on SKOV3 cells through PEA‑15 knockdown by siRNA. Isoalantolactone‑induced autophagic cell death was further confirmed by pretreatment with the autophagy inhibitor 3‑methyladenine (3‑MA). In conclusion, isoalantolactone induced cell cycle arrest and autophagy and inhibited cell proliferation of SKOV3 cells via the upregulated PEA‑15 expression and the phosphorylation of ERK.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI

2 

Bhoola S and Hoskins WJ: Diagnosis and management of epithelial ovarian cancer. Obstet Gynecol. 107:1399–1410. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Siegel R, Ward E, Brawley O and Jemal A: Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 61:212–236. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Yagüe E, Arance A, Kubitza L, O'Hare M, Jat P, Ogilvie CM, Hart IR, Higgins CF and Raguz S: Ability to acquire drug resistance arises early during the tumorigenesis process. Cancer Res. 67:1130–1137. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H and Haga N: Molecular targeting therapy of cancer: Drug resistance, apoptosis and survival signal. Cancer Sci. 94:15–21. 2003. View Article : Google Scholar : PubMed/NCBI

6 

Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C and Gottesman MM: Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 5:219–234. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Ozols RF, Bookman MA, du Bois A, Pfisterer J, Reuss A and Young RC: Intraperitoneal cisplatin therapy in ovarian cancer: Comparison with standard intravenous carboplatin and paclitaxel. Gynecol Oncol. 103:1–6. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Ramirez I, Chon HS and Apte SM: The role of surgery in the management of epithelial ovarian cancer. Cancer Control. 18:22–30. 2011.PubMed/NCBI

9 

Ghantous A, Gali-Muhtasib H, Vuorela H, Saliba NA and Darwiche N: What made sesquiterpene lactones reach cancer clinical trials? Drug Discov Today. 15:668–678. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Zhang S, Won YK, Ong CN and Shen HM: Anti-cancer potential of sesquiterpene lactones: Bioactivity and molecular mechanisms. Curr Med Chem Anticancer Agents. 5:239–249. 2005. View Article : Google Scholar : PubMed/NCBI

11 

Li Y, Ni ZY, Zhu MC, Dong M, Wang SM, Shi QW, Zhang ML, Wang YF, Huo CH, Kiyota H, et al: Antitumour activities of sesquiterpene lactones from Inula helenium and Inula japonica. Z Naturforsch C. 67:375–380. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Khan M, Ding C, Rasul A, Yi F, Li T, Gao H, Gao R, Zhong L, Zhang K, Fang X, et al: Isoalantolactone induces reactive oxygen species mediated apoptosis in pancreatic carcinoma PANC-1 cells. Int J Biol Sci. 8:533–547. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Pal HC, Sehar I, Bhushan S, Gupta BD and Saxena AK: Activation of caspases and poly (ADP-ribose) polymerase cleavage to induce apoptosis in leukemia HL-60 cells by Inula racemosa. Toxicol In Vitro. 24:1599–1609. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Trendafilova A, Chanev C and Todorova M: Ultrasound-assisted extraction of alantolactone and isoalantolactone from Inula helenium roots. Pharmacogn Mag. 6:234–237. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Leist M and Jäättelä M: Four deaths and a funeral: From caspases to alternative mechanisms. Nat Rev Mol Cell Biol. 2:589–598. 2001. View Article : Google Scholar : PubMed/NCBI

16 

Semenza GL: Mitochondrial autophagy: Life and breath of the cell. Autophagy. 4:534–536. 2008. View Article : Google Scholar : PubMed/NCBI

17 

Shintani T and Klionsky DJ: Autophagy in health and disease: A double-edged sword. Science. 306:990–995. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Ito H, Daido S, Kanzawa T, Kondo S and Kondo Y: Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells. Int J Oncol. 26:1401–1410. 2005.PubMed/NCBI

19 

Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E, Domingo D and Yahalom J: A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res. 61:439–444. 2001.PubMed/NCBI

20 

Bartholomeusz C, Rosen D, Wei C, Kazansky A, Yamasaki F, Takahashi T, Itamochi H, Kondo S, Liu J and Ueno NT: PEA-15 induces autophagy in human ovarian cancer cells and is associated with prolonged overall survival. Cancer Res. 68:9302–9310. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Fiory F, Formisano P, Perruolo G and Beguinot F: Frontiers: PED/PEA-15, a multifunctional protein controlling cell survival and glucose metabolism. Am J Physiol Endocrinol Metab. 297:E592–E601. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Rasul A, Yu B, Zhong L, Khan M, Yang H and Ma T: Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy. Oncol Rep. 27:1481–1487. 2012.PubMed/NCBI

23 

Kanzawa T, Kondo Y, Ito H, Kondo S and Germano I: Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res. 63:2103–2108. 2003.PubMed/NCBI

24 

Levine B and Yuan J: Autophagy in cell death: An innocent convict? J Clin Invest. 115:2679–2688. 2005. View Article : Google Scholar : PubMed/NCBI

25 

Kanzawa T, Zhang L, Xiao L, Germano IM, Kondo Y and Kondo S: Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene. 24:980–991. 2005. View Article : Google Scholar

26 

Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H and Levine B: Induction of autophagy and inhibition of tumorigenesis by Beclin 1. Nature. 402:672–676. 1999. View Article : Google Scholar : PubMed/NCBI

27 

Mathew R, Karantza-Wadsworth V and White E: Role of autophagy in cancer. Nat Rev Cancer. 7:961–967. 2007. View Article : Google Scholar : PubMed/NCBI

28 

Chen N and Karantza-Wadsworth V: Role and regulation of autophagy in cancer. Biochim Biophys Acta. 1793:1516–1523. 2009. View Article : Google Scholar : PubMed/NCBI

29 

Corcelle E, Nebout M, Bekri S, Gauthier N, Hofman P, Poujeol P, Fénichel P and Mograbi B: Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. Cancer Res. 66:6861–6870. 2006. View Article : Google Scholar : PubMed/NCBI

30 

Ogier-Denis E, Pattingre S, El Benna J and Codogno P: Erk1/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells. J Biol Chem. 275:39090–39095. 2000. View Article : Google Scholar : PubMed/NCBI

31 

Janssen A and Medema RH: Mitosis as an anti-cancer target. Oncogene. 30:2799–2809. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y and Yoshimori T: Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 152:657–668. 2001. View Article : Google Scholar : PubMed/NCBI

33 

Weidberg H, Shpilka T, Shvets E, Abada A, Shimron F and Elazar Z: LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev Cell. 20:444–454. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y and Kondo S: Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res. 64:4286–4293. 2004. View Article : Google Scholar : PubMed/NCBI

35 

Cao Y and Klionsky DJ: Physiological functions of Atg6/Beclin 1: A unique autophagy-related protein. Cell Res. 17:839–849. 2007. View Article : Google Scholar : PubMed/NCBI

36 

Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC and Levine B: Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics. 59:59–65. 1999. View Article : Google Scholar : PubMed/NCBI

37 

Tanida I, Sou YS, Ezaki J, Minematsu-Ikeguchi N, Ueno T and Kominami E: HsAtg4B/HsApg4B/autophagin-1 cleaves the carboxyl termini of three human Atg8 homologues and delipidates microtubule-associated protein light chain 3- and GABAA receptor-associated protein-phospholipid conjugates. J Biol Chem. 279:36268–36276. 2004. View Article : Google Scholar : PubMed/NCBI

38 

Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y and Yoshimori T: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19:5720–5728. 2000. View Article : Google Scholar : PubMed/NCBI

39 

Renault F, Formstecher E, Callebaut I, Junier MP and Chneiweiss H: The multifunctional protein PEA-15 is involved in the control of apoptosis and cell cycle in astrocytes. Biochem Pharmacol. 66:1581–1588. 2003. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Weng Z, Gao H, Hu J, Fan Y, Wang H and Li L: Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15. Oncol Rep 35: 833-840, 2016.
APA
Weng, Z., Gao, H., Hu, J., Fan, Y., Wang, H., & Li, L. (2016). Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15. Oncology Reports, 35, 833-840. https://doi.org/10.3892/or.2015.4461
MLA
Weng, Z., Gao, H., Hu, J., Fan, Y., Wang, H., Li, L."Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15". Oncology Reports 35.2 (2016): 833-840.
Chicago
Weng, Z., Gao, H., Hu, J., Fan, Y., Wang, H., Li, L."Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15". Oncology Reports 35, no. 2 (2016): 833-840. https://doi.org/10.3892/or.2015.4461
Copy and paste a formatted citation
x
Spandidos Publications style
Weng Z, Gao H, Hu J, Fan Y, Wang H and Li L: Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15. Oncol Rep 35: 833-840, 2016.
APA
Weng, Z., Gao, H., Hu, J., Fan, Y., Wang, H., & Li, L. (2016). Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15. Oncology Reports, 35, 833-840. https://doi.org/10.3892/or.2015.4461
MLA
Weng, Z., Gao, H., Hu, J., Fan, Y., Wang, H., Li, L."Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15". Oncology Reports 35.2 (2016): 833-840.
Chicago
Weng, Z., Gao, H., Hu, J., Fan, Y., Wang, H., Li, L."Isoalantolactone induces autophagic cell death in SKOV3 human ovarian carcinoma cells via upregulation of PEA-15". Oncology Reports 35, no. 2 (2016): 833-840. https://doi.org/10.3892/or.2015.4461
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