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Cellular and Molecular Neurobiology

, Volume 35, Issue 2, pp 175–187 | Cite as

Ficus carica Latex Prevents Invasion Through Induction of Let-7d Expression in GBM Cell Lines

  • Gulcin Tezcan
  • Berrin TuncaEmail author
  • Ahmet Bekar
  • Murat Yalcin
  • Saliha Sahin
  • Ferah Budak
  • Gulsah Cecener
  • Unal Egeli
  • Cevdet Demir
  • Gokcen Guvenc
  • Gozde Yilmaz
  • Leman Gizem Erkan
  • Hulusi Malyer
  • Mevlut Ozgur Taskapilioglu
  • Turkkan Evrensel
  • Ayhan Bilir
Original Research

Abstract

Glioblastoma multiforme (GBM) is one of the deadliest human malignancies. A cure for GBM remains elusive, and the overall survival time is less than 1 year. Thus, the development of more efficient therapeutic approaches for the treatment of these patients is required. Induction of tumor cell death by certain phytochemicals derived from medicinal herbs and dietary plants has become a new frontier for cancer therapy research. Although the cancer suppressive effect of Ficus carica (fig) latex (FCL) has been determined in a few cancer types, the effect of this latex on GBM tumors has not been investigated. Therefore, in the current study, the anti-proliferative activity of FCL and the effect of the FCL–temozolomide (TMZ) combination were tested in the T98G, U-138 MG, and U-87 MG GBM cell lines using the WST-1 assay. The mechanism of cell death was analyzed using Annexin-V/FITC and TUNEL assays, and the effect of FCL on invasion was tested using the chick chorioallantoic membrane assay. To determine the effect of FCL on GBM progression, the expression levels of 40 GBM associated miRNAs were analyzed in T98G cells using RT-qPCR. According to the obtained data, FCL causes cell death in GBM cells with different responses to TMZ, and this effect is synergistically increased in combination with TMZ. In addition, the current study is the first to demonstrate the effect of FCL on modulation of let-7d expression, which may be an important underlying mechanism of the anti-invasive effect of this extract.

Keywords

Ficus carica latex Glioblastoma Temozolomide microRNA Invasion 

Notes

Acknowledgments

This work was supported by the Science Foundation of Uludag University (Project number; UAP(T)-2012/2 and HDP(T)-2013/3). This study was performed as part of G. Tezcan’s PhD thesis project.

Conflict of interest

None.

References

  1. Ahmed W, Khan AQ, Malik A (1988) Two triterpenes from the leaves of Ficus carica. Planta Med 54(5):481CrossRefPubMedGoogle Scholar
  2. Anter J, Romero-Jiménez M, Fernández-Bedmar Z, Villatoro-Pulido M, Analla M, Alonso-Moraga A, Muñoz-Serrano A (2011) Antigenotoxicity, cytotoxicity, and apoptosis induction by apigenin, bisabolol, and protocatechuic acid. J Med Food 14(3):276–283CrossRefPubMedGoogle Scholar
  3. Barbieri I, Pensa S, Pannellini T, Quaglino E, Maritano D, Demaria M, Voster A, Turkson J, Cavallo F, Watson CJ, Provero P, Musiani P, Poli V (2010) Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of Cten. Cancer Res 70(6):2558–2567CrossRefPubMedGoogle Scholar
  4. Canal JR, Torres MD, Romero A, Pérez C (2000) A chloroform extract obtained from a decoction of Ficus carica leaves improves the cholesterolaemic status of rats with streptozotocin-induced diabetes. Acta Physiol Hung 87(1):71–76CrossRefPubMedGoogle Scholar
  5. Chen Z, Cheng Q, Ma Z, Xi H, Peng R, Jiang B (2013) Overexpression of RKIP inhibits cell invasion in glioma cell lines through upregulation of miR-98. Biomed Res Int. 2013:695179PubMedCentralPubMedGoogle Scholar
  6. Conforti F, Menichini G, Zanfini L, Tundis R, Statti GA, Provenzano E, Menichini F, Somma F, Alfano C (2012) Evaluation of phototoxic potential of aerial components of the fig tree against human melanoma. Cell Prolif. 45:279–285. doi: 10.1111/j.1365-2184.2012.00816.x CrossRefPubMedGoogle Scholar
  7. Dahiya N, Sherman-Baust CA, Wang TL, Davidson B, Shih IeM, Zhang Y, Wood W 3rd, Becker KG, Morin PJ (2008) MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PLoS One 3(6):e2436CrossRefPubMedCentralPubMedGoogle Scholar
  8. Di Leva G, Croce CM (2010) Roles of small RNAs in tumor formation. Trends Mol Med 16:257–267CrossRefPubMedCentralPubMedGoogle Scholar
  9. Fang B (2014) Genetic interactions of STAT3 and anticancer drug development. Cancers (Basel) 6(1):494–525CrossRefGoogle Scholar
  10. Gandellini P, Profumo V, Folini M, Zaffaroni N (2011) MicroRNAs as new therapeutic targets and tools in cancer. Expert OpinTher Targets 15:265–279CrossRefGoogle Scholar
  11. Hashemi SA, Abediankenari S, Ghasemi M, Azadbakht M, Yousefzadeh Y, Dehpour AA (2011) The effect of fig tree latex (Ficus carica) on stomach cancer line. Iran Red Crescent Med J. 13(4):272–275PubMedCentralPubMedGoogle Scholar
  12. Heldin CH, Vanlandewijck M, Moustakas A (2012) Regulation of EMT by TGFβ in cancer. FEBS Lett 586(14):1959–1970CrossRefPubMedGoogle Scholar
  13. Hulleman E, Helin K (2005) Molecular mechanisms in gliomagenesis. Adv Cancer Res 94:1–27CrossRefPubMedGoogle Scholar
  14. Ishikawa F, Kaneko E, Sugimoto T, Ishijima T, Wakamatsu M, Yuasa A, Sampei R, Mori K, Nose K, Shibanuma M (2014) A mitochondrial thioredoxin-sensitive mechanism regulates TGF-β-mediated gene expression associated with epithelial-mesenchymal transition. Biochem Biophys Res Commun 443(3):821–827CrossRefPubMedGoogle Scholar
  15. Kang Z, Zhu H, Jiang W, Zhang S (2013) Protocatechuic acid induces angiogenesis through PI3K-Akt-eNOS-VEGF signalling pathway. Basic Clin Pharmacol Toxicol 113(4):221–227CrossRefPubMedGoogle Scholar
  16. Khor TO, Keum YS, Lin W, Kim JH, Hu R, Shen G, Xu C, Gopalakrishnan A, Reddy B, Zheng X, Conney AH, Kong AN (2006) Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC-3 prostate xenografts in immunodeficient mice. Cancer Res 66(2):613–621CrossRefPubMedGoogle Scholar
  17. Kong AN, Zhang C, Su ZY (2013) Targeting epigenetics for cancer prevention by dietary cancer preventive compounds—the case of miRNA. Cancer Prev Res (Phila). 6(7):622–624CrossRefPubMedCentralPubMedGoogle Scholar
  18. Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, Sabel M, Steinbach JP, Heese O, Reifenberger G, Weller M, Schackert G (2007) Long-term survival with glioblastoma multiforme. Brain 130:2596–2606CrossRefPubMedGoogle Scholar
  19. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta DeltaC(T)) Method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  20. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109CrossRefPubMedCentralPubMedGoogle Scholar
  21. Mawa S, Husain K, Jantan I (2013) Ficus carica L. (Moraceae): phytochemistry, traditional uses and biological activities. Evid Based Complement Alternat Med 2013:974256PubMedCentralPubMedGoogle Scholar
  22. Menichini G, Alfano C, Provenzano E, Marrelli M, Statti GA, Somma F, Menichini F, Conforti F (2012) Fig latex (Ficus carica L. cultivar Dottato) in combination with UV irradiation decreases the viability of A375 melanoma cells in vitro. Anticancer Agents Med Chem. 12(8):959–965CrossRefPubMedGoogle Scholar
  23. Mijatovic SA, Timotijevic GS, Miljkovic DM, Radovic JM, Maksimovic- Ivanic DD, Dekanski DP, Stosic-Grujicic SD (2011) Multiple antimelanoma potential of dry olive leaf extract. Int J Cancer 128:1955–1965CrossRefPubMedGoogle Scholar
  24. Mu G, Liu H, Zhou F, Xu X, Jiang H, Wang Y, Qu Y (2010) Correlation of overexpression of HMGA1 and HMGA2 with poor tumor differentiation, invasion, and proliferation associated with let-7 down-regulation in retinoblastomas. Hum Pathol 41(4):493–502CrossRefPubMedGoogle Scholar
  25. Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477CrossRefPubMedGoogle Scholar
  26. O’Hara AJ, Wang L, Dezube BJ, Harrington WJ Jr, Damania B, Dittmer DP (2009) Tumor suppressor microRNAs are underrepresented in primary effusion lymphoma and Kaposi sarcoma. Blood 113:5938–5941CrossRefPubMedCentralPubMedGoogle Scholar
  27. Paluszczak J, Krajka-Kuzniak V, Baer-Dubowska W (2010) The effect of dietary polyphenols on the epigenetic regulation of gene expression in MCF7 breast cancer cells. Toxicol Lett 192(2):119–125CrossRefPubMedGoogle Scholar
  28. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7(6):415–428CrossRefPubMedGoogle Scholar
  29. Ranger JJ, Levy DE, Shahalizadeh S, Hallett M, Muller WJ (2009) Identification of a Stat3-dependent transcription regulatory network involved in metastatic progression. Cancer Res 69(17):6823–6830CrossRefPubMedCentralPubMedGoogle Scholar
  30. Rubnov S, Kashman Y, Rabinowitz R, Schlesinger M, Mechoulam R (2001) Suppressors of cancer cell proliferation from fig (Ficus carica) resin: isolation and structure elucidation. J Nat Prod 64(7):993–996CrossRefPubMedGoogle Scholar
  31. Sanli T, Strano S, Muti P (2013) Lifestyle factors and microRNAs: a new paradigm in cancer chemoprevention. Microrna 2(2):82–90CrossRefPubMedGoogle Scholar
  32. Serraclara A, Hawkins F, Pérez C, Domínguez E, Campillo JE, Torres MD (1998) Hypoglycemic action of an oral fig-leaf decoction in type-I diabetic patients. Diabetes Res Clin Pract 39(1):19–22CrossRefPubMedGoogle Scholar
  33. Sethi S, Li Y, Sarkar FH (2013) Regulating miRNA by natural agents as a new strategy for cancer treatment. Curr Drug Targets 14(10):1167–1174CrossRefPubMedCentralPubMedGoogle Scholar
  34. Spilioti E, Jaakkola M, Tolonen T, Lipponen M, Virtanen V, Chinou I, Kassi E, Karabournioti S, Moutsatsou P (2014) Phenolic acid composition, antiatherogenic and anticancer potential of honeys derived from various regions in Greece. PLoS One 9(4):e94860CrossRefPubMedCentralPubMedGoogle Scholar
  35. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  36. Sugimura K, Miyata H, Tanaka K, Hamano R, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Takiguchi S, Mori M, Doki Y (2012) Let-7 expression is a significant determinant of response to chemotherapy through the regulation of IL-6/STAT3 pathway in esophageal squamous cell carcinoma. Clin Cancer Res 18(18):5144–5153CrossRefPubMedGoogle Scholar
  37. Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 1 64(11):3753–3756CrossRefGoogle Scholar
  38. Teng TS, Lin B, Manser E, Ng DC, Cao X (2009) Stat3 promotes directional cell migration by regulating Rac1 activity via its activator betaPIX. J Cell Sci 122(Pt 22):4150–4159CrossRefPubMedGoogle Scholar
  39. Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A (2006) Transforming growth factor-beta employs HMGA2 to elicit epithelial mesenchymal transition. J Cell Biol 174:175–183CrossRefPubMedCentralPubMedGoogle Scholar
  40. Tunca B, Tezcan G, Cecener G, Egeli U, Ak S, Malyer H, Tumen G, Bilir A (2012) Olea europaea leaf extract alters microRNA expression in human glioblastoma cells. J Cancer Res Clin Oncol 138(11):1831–1844CrossRefPubMedGoogle Scholar
  41. Wang D, Xia M, Yan X, Li D, Wang L, Xu Y, Jin T, Ling W (2012) Gut microbiota metabolism of anthocyanin promotes reverse cholesterol transport in mice via repressing miRNA-10b. Circ Res 111(8):967–981CrossRefPubMedGoogle Scholar
  42. Xi YN, Xin XY, Ye HM (2014) Effects of HMGA2 on malignant degree, invasion, metastasis, proliferation and cellular morphology of ovarian cancer cells. Asian Pac J Trop Med 7(4):289–292CrossRefPubMedGoogle Scholar
  43. Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, Gritsko T, Turkson J, Kay H, Semenza GL, Cheng JQ, Jove R, Yu H (2005) Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24(36):5552–5560CrossRefPubMedGoogle Scholar
  44. Lin HH, Chen JH, Chou FP, Wang CJ (2011) Protocatechuic acid inhibits cancer cell metastasis involving the down-regulation of Ras/Akt/NF-κB pathway and MMP-2 production by targeting RhoB activation. Br J Pharmacol. 162(1):237–254CrossRefPubMedCentralPubMedGoogle Scholar
  45. Pérez C, Canal JR, Campillo JE, Romero A, Torres MD (1999) Hypotriglyceridaemic activity of Ficus carica leaves in experimental hypertriglyceridaemic rats. Phytother Res. 13(3):188–191CrossRefPubMedGoogle Scholar
  46. Yin MC, Lin CC, Wu HC, Tsao SM, Hsu CK (2009) Apoptotic effects of protocatechuic acid in human breast, lung, liver, cervix, and prostate cancer cells: potential mechanisms of action. J Agric Food Chem 57(14):6468–6473CrossRefPubMedGoogle Scholar
  47. Yoshino A, Ogino A, Yachi K, Ohta T, Fukushima T, Watanabe T, Katayama Y, Okamoto Y, Naruse N, Sano E, Tsumoto K (2010) Gene expression profiling predicts response to temozolomide in malignant gliomas. Int J Oncol 36:1367–1377CrossRefPubMedGoogle Scholar
  48. Zheng Y, Yang W, Aldape K, He J, Lu Z (2013) Epidermal growth factor (EGF)-enhanced vascular cell adhesion molecule-1 (VCAM-1) expression promotes macrophage and glioblastoma cell interaction and tumor cell invasion. J Biol Chem 288(44):31488–31495CrossRefPubMedCentralPubMedGoogle Scholar
  49. Zushi S, Shinomura Y, Kiyohara T, Miyazaki Y, Kondo S, Sugimachi M, Higashimoto Y, Kanayama S, Matsuzawa Y (1998) STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. Int J Cancer 78(3):326–330CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Gulcin Tezcan
    • 1
  • Berrin Tunca
    • 1
    Email author
  • Ahmet Bekar
    • 2
  • Murat Yalcin
    • 3
  • Saliha Sahin
    • 4
  • Ferah Budak
    • 5
  • Gulsah Cecener
    • 1
  • Unal Egeli
    • 1
  • Cevdet Demir
    • 4
  • Gokcen Guvenc
    • 3
  • Gozde Yilmaz
    • 3
  • Leman Gizem Erkan
    • 3
  • Hulusi Malyer
    • 6
  • Mevlut Ozgur Taskapilioglu
    • 2
  • Turkkan Evrensel
    • 7
  • Ayhan Bilir
    • 8
  1. 1.Department of Medical Biology, Medical FacultyUludag UniversityBursaTurkey
  2. 2.Department of Neurosurgery, Medical FacultyUludag UniversityBursaTurkey
  3. 3.Department of Physiology, Veterinary Medicine FacultyUludag UniversityBursaTurkey
  4. 4.Department of Chemistry, Science FacultyUludag UniversityBursaTurkey
  5. 5.Department of Microbiology, Medical FacultyUludag UniversityBursaTurkey
  6. 6.Department of Biology, Science FacultyUludag UniversityBursaTurkey
  7. 7.Department of Medical Oncology, Medical FacultyUludag UniversityBursaTurkey
  8. 8.Department of Histology and Embryology, Medical FacultyZirve UniversityGaziantepTurkey

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