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
September-2016 Volume 49 Issue 3

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
September-2016 Volume 49 Issue 3

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

The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling

  • Authors:
    • Dorrah Deeb
    • Xiaohua Gao
    • Yongbo Liu
    • Yiguan Zhang
    • Jiajiu Shaw
    • Frederick A. Valeriote
    • Subhash C. Gautam
  • View Affiliations / Copyright

    Affiliations: Department of Surgery, Henry Ford Health System, Detroit, MI, USA, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA
  • Pages: 1139-1147
    |
    Published online on: June 29, 2016
       https://doi.org/10.3892/ijo.2016.3587
  • 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

Pancreatic ductal adenocarcinoma (PDA) remains one of the most difficult to treat of all malignancies. Multimodality regimens provide only short-term symptomatic improvement with minor impact on survival, underscoring the urgent need for novel therapeutics and treatment strategies for PDA. Trichothecenes are powerful mycotoxins that inhibit protein synthesis and induce ribotoxic stress response in mammalian cells. Verrucarin A (VC-A) is a Type D macrocyclic mycotoxin which inhibited cell proliferation and induced apoptosis in breast cancer cells. However, the antitumor activity of VC-A for PDA cells has not been investigated. Here we show potent antitumor activity and the mechanism of action of VC-A in PDA cell lines. VC-A strongly inhibited the proliferation and arrested cells in the S phase of the cell cycle. The blocking of cell cycle progression by VC-A was associated with the inhibition of cell cycle regulatory proteins cyclin D1, cyclin E, cyclin-dependent kinases (cdks) cdk2, cdk4 and cdk inhibitor WAF1/21. VC-A induced apoptosis in PDA cells as indicated by the increased Annexin V FITC-binding, cleavage of poly(ADP-ribose) polymerase‑1 (PARP-1) and procaspases-3, -8 and -9. VC-A also induced mitochondrial depolarization and release of cytochrome c and it inhibited Bcl-2 family proteins that regulate apoptosis (Bcl-2, Bcl-xL, Bax and Bad). In addition, VC-A reduced the levels of inhibitors of apoptosis survivin and c-IAP-2. Finally, VC-A downregulated the expression of prosurvival phospho-Akt (p-Akt), nuclear factor κB (NF-κB) (p65) and mammalian target of rapamycin (p-mTOR) signaling proteins and their downstream mediators. Together, these results demonstrated strong antiproliferative and apoptosis-inducing activity of verrucarin A for PDA cells through cell cycle arrest and inhibition of the prosurvival (antiapoptotic) AKT/NF-κB/mTOR signaling.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

National Cancer Institute. Pancreatic Cancer-National Cancer Institute, U.S. National Institutes of Health. Cancer. https://www.cancer.gov/types/pancreatic. Accessed 06-04-2010

2 

Maitra A and Hruban RH: Pancreatic cancer. Annu Rev Pathol. 3:157–188. 2008. View Article : Google Scholar

3 

Li D, Xie K, Wolff R and Abbruzzese JL: Pancreatic cancer. Lancet. 363:1049–1057. 2004. View Article : Google Scholar : PubMed/NCBI

4 

Mulcahy MF, Wahl AO and Small W Jr: The current status of combined radiotherapy and chemotherapy for locally advanced or resected pancreas cancer. J Natl Compr Canc Netw. 3:637–642. 2005.PubMed/NCBI

5 

Pino SM, Xiong HQ, McConkey D and Abbruzzese JL: Novel therapies for pancreatic adenocarcinoma. Curr Oncol Rep. 6:199–206. 2004. View Article : Google Scholar : PubMed/NCBI

6 

Vaccaro V, Sperduti I and Milella M: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 365:768–769; author reply 769. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Pestka JJ, Yike I, Dearborn DG, Ward MD and Harkema JR: Stachybotrys chartarum, trichothecene mycotoxins, and damp building-related illness: New insights into a public health enigma. Toxicol Sci. 104:4–26. 2008. View Article : Google Scholar

8 

Hossain MA, Ahmed MS and Ghannoum MA: Attributes of Stachybotrys chartarum and its association with human disease. J Allergy Clin Immunol. 113:200–208; quiz 209. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Kilburn KH: Role of molds and mycotoxins in being sick in buildings: Neurobehavioral and pulmonary impairment. Adv Appl Microbiol. 55:339–359. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Hardin BD, Kelman BJ and Saxon A: Adverse human health effects associated with molds in the indoor environment. J Occup Environ Med. 45:470–478. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Leatherman DL and Middlebrook JL: Effect of emetine on T-2 toxin-induced inhibition of protein synthesis in mammalian cells. J Pharmacol Exp Ther. 266:741–748. 1993.PubMed/NCBI

12 

Ge HM, Jiao RH, Zhang YF, Zhang J, Wang YR and Tan RX: Cytotoxicity and phytotoxicity of trichothecene macrolides from Myrothecium gramminum. Planta Med. 75:227–229. 2009. View Article : Google Scholar

13 

Abbas HK, Johnson BB, Shier WT, Tak H, Jarvis BB and Boyette CD: Phytotoxicity and mammalian cytotoxicity of macrocyclic trichothecene mycotoxins from Myrothecium verrucaria. Phytochemistry. 59:309–313. 2002. View Article : Google Scholar : PubMed/NCBI

14 

Shifrin VI and Anderson P: Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. J Biol Chem. 274:13985–13992. 1999. View Article : Google Scholar : PubMed/NCBI

15 

Chung YJ, Jarvis B and Pestka J: Modulation of lipopolysaccharide-induced proinflammatory cytokine production by satratoxins and other macrocyclic trichothecenes in the murine macrophage. J Toxicol Environ Health A. 66:379–391. 2003. View Article : Google Scholar : PubMed/NCBI

16 

Hughes BJ, Taylor MJ and Sharma RP: Effects of verrucarin A and roridin A, macrocyclic trichothecene mycotoxins, on the murine immune system. Immunopharmacology. 16:79–87. 1988. View Article : Google Scholar : PubMed/NCBI

17 

Palanivel K, Kanimozhi V and Kadalmani B: Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent p38MAPK activation in the human breast cancer cell line MCF-7. Tumour Biol. 35:10159–10167. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Palanivel K, Kanimozhi V, Kadalmani B and Akbarsha MA: Verrucarin A induces apoptosis through ROS-mediated EGFR/MAPK/Akt signaling pathways in MDA-MB-231 breast cancer cells. J Cell Biochem. 115:2022–2032. 2014.PubMed/NCBI

19 

Woldemichael GM, Turbyville TJ, Vasselli JR, Linehan WM and McMahon JB: Lack of a functional VHL gene product sensitizes renal cell carcinoma cells to the apoptotic effects of the protein synthesis inhibitor verrucarin A. Neoplasia. 14:771–777. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Yang GH, Jarvis BB, Chung YJ and Pestka JJ: Apoptosis induction by the satratoxins and other trichothecene mycotoxins: Relationship to ERK, p38 MAPK, and SAPK/JNK activation. Toxicol Appl Pharmacol. 164:149–160. 2000. View Article : Google Scholar : PubMed/NCBI

21 

Amagata T, Rath C, Rigot JF, Tarlov N, Tenney K, Valeriote FA and Crews P: Structures and cytotoxic properties of trichoverroids and their macrolide analogues produced by saltwater culture of Myrothecium verrucaria. J Med Chem. 46:4342–4350. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Chin YW, Balunas MJ, Chai HB and Kinghorn AD: Drug discovery from natural sources. AAPS J. 8:E239–E253. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Itokawa H, Morris-Natschke SL, Akiyama T and Lee KH: Plant-derived natural product research aimed at new drug discovery. J Nat Med. 62:263–280. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Kerr JF, Winterford CM and Harmon BV: Apoptosis. Its significance in cancer and cancer therapy. Cancer. 73:2013–2026. 1994. View Article : Google Scholar : PubMed/NCBI

25 

Cusack JC Jr: Overcoming antiapoptotic responses to promote chemosensitivity in metastatic colorectal cancer to the liver. Ann Surg Oncol. 10:852–862. 2003. View Article : Google Scholar : PubMed/NCBI

26 

Ramanathan B, Jan KY, Chen CH, Hour TC, Yu HJ and Pu YS: Resistance to paclitaxel is proportional to cellular total antioxidant capacity. Cancer Res. 65:8455–8460. 2005. View Article : Google Scholar : PubMed/NCBI

27 

Sun Y and Rigas B: The thioredoxin system mediates redox-induced cell death in human colon cancer cells: Implications for the mechanism of action of anticancer agents. Cancer Res. 68:8269–8277. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Chao DT and Korsmeyer SJ: BCL-2 family: Regulators of cell death. Annu Rev Immunol. 16:395–419. 1998. View Article : Google Scholar : PubMed/NCBI

29 

Green DR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI

30 

Deveraux QL and Reed JC: IAP family proteins - suppressors of apoptosis. Genes Dev. 13:239–252. 1999. View Article : Google Scholar : PubMed/NCBI

31 

Vivanco I and Sawyers CL: The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI

32 

Altomare DA and Testa JR: Perturbations of the AKT signaling pathway in human cancer. Oncogene. 24:7455–7464. 2005. View Article : Google Scholar : PubMed/NCBI

33 

Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 91:231–241. 1997. View Article : Google Scholar : PubMed/NCBI

34 

Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 96:857–868. 1999. View Article : Google Scholar : PubMed/NCBI

35 

Mayo MW and Baldwin AS: The transcription factor NF-kappaB: Control of oncogenesis and cancer therapy resistance. Biochim Biophys Acta. 1470:M55–M62. 2000.PubMed/NCBI

36 

Bjornsti MA and Houghton PJ: The TOR pathway: A target for cancer therapy. Nat Rev Cancer. 4:335–348. 2004. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Deeb D, Gao X, Liu Y, Zhang Y, Shaw J, Valeriote FA and Gautam SC: The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling. Int J Oncol 49: 1139-1147, 2016.
APA
Deeb, D., Gao, X., Liu, Y., Zhang, Y., Shaw, J., Valeriote, F.A., & Gautam, S.C. (2016). The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling. International Journal of Oncology, 49, 1139-1147. https://doi.org/10.3892/ijo.2016.3587
MLA
Deeb, D., Gao, X., Liu, Y., Zhang, Y., Shaw, J., Valeriote, F. A., Gautam, S. C."The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling". International Journal of Oncology 49.3 (2016): 1139-1147.
Chicago
Deeb, D., Gao, X., Liu, Y., Zhang, Y., Shaw, J., Valeriote, F. A., Gautam, S. C."The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling". International Journal of Oncology 49, no. 3 (2016): 1139-1147. https://doi.org/10.3892/ijo.2016.3587
Copy and paste a formatted citation
x
Spandidos Publications style
Deeb D, Gao X, Liu Y, Zhang Y, Shaw J, Valeriote FA and Gautam SC: The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling. Int J Oncol 49: 1139-1147, 2016.
APA
Deeb, D., Gao, X., Liu, Y., Zhang, Y., Shaw, J., Valeriote, F.A., & Gautam, S.C. (2016). The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling. International Journal of Oncology, 49, 1139-1147. https://doi.org/10.3892/ijo.2016.3587
MLA
Deeb, D., Gao, X., Liu, Y., Zhang, Y., Shaw, J., Valeriote, F. A., Gautam, S. C."The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling". International Journal of Oncology 49.3 (2016): 1139-1147.
Chicago
Deeb, D., Gao, X., Liu, Y., Zhang, Y., Shaw, J., Valeriote, F. A., Gautam, S. C."The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling". International Journal of Oncology 49, no. 3 (2016): 1139-1147. https://doi.org/10.3892/ijo.2016.3587
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