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Tumor Biology

, Volume 37, Issue 12, pp 15489–15494 | Cite as

Fluorouracil induces autophagy-related gastric carcinoma cell death through Beclin-1 upregulation by miR-30 suppression

Original Article

Abstract

The molecular mechanisms underlying the anti-cancer effects of chemotherapy drugs are not completely understood. Here, we studied the effects of fluorouracil (5-FU) on gastric carcinoma (GC) cells. We found that 5-FU dose-dependently inhibited the growth of GC cells, in either a cell counting kit-8 (CCK-8) assay or a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Moreover, autophagy-associated protein 6 (ATG6) or Beclin-1 was dose-dependently activated by 5-FU in GC cells. Further, microRNA (miR)-30 was found to be regulated by 5-FU, and bioinformatics analysis showed that miR-30 targeted the 3′-UTR of Beclin-1 to inhibit its translation. Together, these data suggest that 5-FU may suppress miR-30 to upregulate Beclin-1 to induce autophagic cell death and cell proliferation arrest in GC cells.

Keywords

Gastric carcinoma (GC) Fluorouracil (5-FU) Beclin-1 miR-30 

Notes

Conflict of interest

None

References

  1. 1.
    Wu W, Ding H, Cao J, Zhang W. Fbxl5 inhibits metastasis of gastric cancer through suppressing snail1. Cell Physiol Biochem. 2015;35:1764–72.CrossRefPubMedGoogle Scholar
  2. 2.
    Attoub S, Karam SM, Nemmar A, Arafat K, John A, Al-Dhaheri W, et al. Short-term effects of oral administration of pistacia lentiscus oil on tissue-specific toxicity and drug metabolizing enzymes in mice. Cell Physiol Biochem. 2014;33:1400–10.CrossRefPubMedGoogle Scholar
  3. 3.
    Xu XY, Zhang LJ, Yu YQ, Zhang XT, Huang WJ, Nie XC, et al. Down-regulated mac30 expression inhibits proliferation and mobility of human gastric cancer cells. Cell Physiol Biochem. 2014;33:1359–68.CrossRefPubMedGoogle Scholar
  4. 4.
    Wang Y, Gao S, Liu G, Jia R, Fan D, Feng X. Microarray expression profile analysis of long non-coding rnas in human gastric cardiac adenocarcinoma. Cell Physiol Biochem. 2014;33:1225–38.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhou X, Xia Y, Su J, Zhang G. Down-regulation of mir-141 induced by helicobacter pylori promotes the invasion of gastric cancer by targeting stat4. Cell Physiol Biochem. 2014;33:1003–12.CrossRefPubMedGoogle Scholar
  6. 6.
    Sankpal UT, Lee CM, Connelly SF, Kayaleh O, Eslin D, Sutphin R, et al. Cellular and organismal toxicity of the anti-cancer small molecule, tolfenamic acid: a pre-clinical evaluation. Cell Physiol Biochem. 2013;32:675–86.CrossRefPubMedGoogle Scholar
  7. 7.
    Cui Y, Chen J, He Z, Xiao Y. Suz12 depletion suppresses the proliferation of gastric cancer cells. Cell Physiol Biochem. 2013;31:778–84.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhao X, Li X, Yuan H. Micrornas in gastric cancer invasion and metastasis. Front Biosci. 2013;18:803–10.CrossRefGoogle Scholar
  9. 9.
    Liu G, Jiang C, Li D, Wang R, Wang W. Mirna-34a inhibits egfr-signaling-dependent mmp7 activation in gastric cancer. Tumour Biol. 2014;35:9801–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Mao D, Zhang Y, Lu H, Zhang H. Molecular basis underlying inhibition of metastasis of gastric cancer by anti-vegfa treatment. Tumour Biol. 2014;35:8217–23.CrossRefPubMedGoogle Scholar
  11. 11.
    Ye Y, Zhou X, Li X, Tang Y, Sun Y, Fang J. Inhibition of epidermal growth factor receptor signaling prohibits metastasis of gastric cancer via downregulation of mmp7 and mmp13. Tumour Biol. 2014;35:10891–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhao Z, Han F, Yang S, Wu J, Zhan W. Oxamate-mediated inhibition of lactate dehydrogenase induces protective autophagy in gastric cancer cells: involvement of the akt-mtor signaling pathway. Cancer Lett. 2015;358:17–26.CrossRefPubMedGoogle Scholar
  13. 13.
    Ge J, Chen Z, Huang J, Chen J, Yuan W, Deng Z, et al. Upregulation of autophagy-related gene-5 (atg-5) is associated with chemoresistance in human gastric cancer. PLoS One. 2014;9, e110293.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hosogi S, Kusuzaki K, Inui T, Wang X, Marunaka Y. Cytosolic chloride ion is a key factor in lysosomal acidification and function of autophagy in human gastric cancer cell. J Cell Mol Med. 2014;18:1124–33.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Liu M, Li CM, Chen ZF, Ji R, Guo QH, Li Q, et al. Celecoxib regulates apoptosis and autophagy via the pi3k/akt signaling pathway in sgc-7901 gastric cancer cells. Int J Mol Med. 2014;33:1451–8.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Tang C, Yang L, Jiang X, Xu C, Wang M, Wang Q, et al. Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells. Biochem Biophys Res Commun. 2014;446:105–12.CrossRefPubMedGoogle Scholar
  17. 17.
    Green DR, Levine B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell. 2014;157:65–75.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Guo JY, Xia B, White E. Autophagy-mediated tumor promotion. Cell. 2013;155:1216–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12:401–10.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–42.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang J, Hummersone M, Matthews CS, Stevens MF, Bradshaw TD. N3-substituted temozolomide analogs overcome methylguanine-DNA methyltransferase and mismatch repair precipitating apoptotic and autophagic cancer cell death. Oncology. 2015;88:28–48.CrossRefPubMedGoogle Scholar
  22. 22.
    Di Leva G, Croce CM. Mirna profiling of cancer. Curr Opin Genet Dev. 2013;23:3–11.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Pereira DM, Rodrigues PM, Borralho PM, Rodrigues CM. Delivering the promise of mirna cancer therapeutics. Drug Discov Today. 2013;18:282–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Mei Q, Li F, Quan H, Liu Y, Xu H. Busulfan inhibits growth of human osteosarcoma through mir-200 family micrornas in vitro and in vivo. Cancer Sci. 2014;105:755–62.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wang F, Xiao W, Sun J, Han D, Zhu Y. Mirna-181c inhibits egfr-signaling-dependent mmp9 activation via suppressing akt phosphorylation in glioblastoma. Tumour Biol. 2014;35:8653–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Ouzounova M, Vuong T, Ancey PB, Ferrand M, Durand G, Le-Calvez Kelm F, et al. Microrna mir-30 family regulates non-attachment growth of breast cancer cells. BMC Genomics. 2013;14:139.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kao CJ, Martiniez A, Shi XB, Yang J, Evans CP, Dobi A, et al. Mir-30 as a tumor suppressor connects egf/src signal to erg and emt. Oncogene. 2014;33:2495–503.CrossRefPubMedGoogle Scholar
  28. 28.
    Yu F, Deng H, Yao H, Liu Q, Su F, Song E. Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells. Oncogene. 2010;29:4194–204.CrossRefPubMedGoogle Scholar
  29. 29.
    Martinez I, Cazalla D, Almstead LL, Steitz JA, DiMaio D. Mir-29 and mir-30 regulate b-myb expression during cellular senescence. Proc Natl Acad Sci U S A. 2011;108:522–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Coronnello C, Benos PV. Comir: combinatorial microrna target prediction tool. Nucleic Acids Res. 2013;41:W159–64.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gewirtz DA. Autophagy and senescence in cancer therapy. J Cell Physiol. 2014;229:6–9.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Gastrointestinal SurgerySichuan Provincial People’s HospitalChengduChina

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