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Leaf Extract from European Olive (Olea europaea L.) Post-Transcriptionally Suppresses the Epithelial-Mesenchymal Transition and Sensitizes Gastric Cancer Cells to Chemotherapy

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Abstract

The overall survival of patients with the advanced and recurrent gastric cancer (GC) remains unfavorable. In particular, this is due to cancer spreading and resistance to chemotherapy associated with the epithelial-mesenchymal transition (EMT) of tumor cells. EMT can be identified by the transcriptome profiling of GC for EMT markers. Indeed, analysis of the TCGA and GTEx databases (n = 408) and a cohort of GC patients (n = 43) revealed that expression of the CDH2 gene was significantly decreased in the tumors vs. non-tumor tissues and correlated with the overall survival of GC patients. Expression of the EMT-promoting transcription factors SNAIL and ZEB1 was significantly increased in GC. These data suggest that targeting the EMT might be an attractive therapeutic approach for patients with GC. Previously, we demonstrated a potent anti-cancer activity of the olive leaf extract (OLE). However, its effect on the EMT regulation in GC remained unknown. Here, we showed that OLE efficiently potentiated the inhibitory effect of the chemotherapeutic agents 5-fluorouracil (5-FU) and cisplatin (Cis) on the EMT and their pro-apoptotic activity, as was demonstrated by changes in the expression of the EMT markers (E- and N-cadherins, vimentin, claudin-1) in GC cells treated with the aforementioned chemotherapeutic agents in the presence of OLE. Thus, culturing GC cells with 5-FU + OLE or Cis + OLE attenuated the invasive properties of cancer cells. Importantly, upregulation of expression of the apoptotic markers (PARP cleaved form) and increase in the number of cells undergoing apoptosis (annexin V-positive) were observed for GC cells treated with a combination of OLE and 5-FU or Cis. Collectively, our data illustrate that OLE efficiently interferes with the EMT in GC cells and potentiates the pro-apoptotic activity of certain chemotherapeutic agents used for GC therapy.

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Acknowledgments

The authors thank Deniz Gülkaya from Bursa Uludag University Department of Immunology for assistance in flow cytometry. The authors are grateful to Assoc. Prof. Gurler Akpinar and Prof. Murat Kasap from Kocaeli University, Department of Medical Biology, for technical support. M.E. is supported by the 100/2000 grant from the Council of Higher Education as a PhD Scholar in Molecular Biology and Genetics (Gene Therapy and Genome Studies). The study was also supported by the Kazan Federal University, Ministry of Health of the Russian Federation and Strategic Academic Leadership Program (PRIORITY-2030).

Funding

This study was supported by the Science Foundation of Bursa Uludag University TKO-2020-175 and by the Russian Science Foundation (project no. 20-15-00001).

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Authors and Affiliations

  1. Department of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey

    Cagla Tekin, Melis Ercelik & Berrin Tunca

  2. Department of Pathology, Kazan State Medical University, Kazan, Russia

    Pavel Dunaev, Aigul Galembikova & Sergei Boichuk

  3. Department of Fundamental Sciences, Faculty of Dentistry, Bursa Uludag University, Bursa, Turkey

    Gulcin Tezcan

  4. Inegol Vocation School, Bursa Uludag University, Bursa, Turkey

    Secil Ak Aksoy

  5. Experimental Animal Breeding and Research Unit, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey

    Secil Ak Aksoy

  6. Department of Immunology, Medical Faculty, Bursa Uludag University, Bursa, Turkey

    Ferah Budak

  7. Department of General Surgery, Medical Faculty, Bursa Uludag University, Bursa, Turkey

    Ozgen Isık

  8. Department of Pathology, Medical Faculty, Bursa Uludag University, Bursa, Turkey

    Nesrin Ugras

  9. Department of Radiotherapy and Radiology, Russian Medical Academy of Continuous Professional Education, Moscow, Russia

    Sergei Boichuk

  10. “Biomarker” Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia

    Sergei Boichuk

Authors
  1. Cagla Tekin
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  2. Melis Ercelik
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  3. Pavel Dunaev
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  4. Aigul Galembikova
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  5. Gulcin Tezcan
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  6. Secil Ak Aksoy
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  10. Sergei Boichuk
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  11. Berrin Tunca
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Contributions

C.T., M.E., G.T., B.T., and S.B. developed the study concept; C.T., M.E., G.T., S.A.A., O.I., N.U., and B.T. collected and reviewed the data; C.T., M.E., G.T., S.A.A., P.D., and A.G. performed the experiments; C.T., M.E., G.T., S.A.A., P.D., A.G., F.B., B.T., and S.B. developed the methodology, O.I. administered the project; G.T., F.B., O.I., N.U., and B.T. supervised the study; C.T., M.E., G.T., P.D., A.G., O.I., N.U., B.T., and S.B. validated the data; C.T., M.E., G.T., S.A.A., F.B., and B.T. visualization; C.T., M.E., G.T., S.A.A., and B.T. wrote the original draft; C.T., G.T., and S.B. reviewed and edited the manuscript.

Corresponding authors

Correspondence to Sergei Boichuk or Berrin Tunca.

Ethics declarations

The procedures performed in studies involving biological material of human participants comply with the institutional and national research committee (name of institute/committee) and the 1964 Helsinki Declaration and subsequent amendments or comparable ethical standards. This study was approved by the local Ethics Committee of Bursa Uludag University (decision number 2019-6/32). The authors of this work declare that they have no conflicts of interest.

Additional information

Data availability statement. All data and materials are available and could be obtained from the corresponding author Tunca B.

Informed consent. Informed consent was obtained from all subjects involved in the study.

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Tekin, C., Ercelik, M., Dunaev, P. et al. Leaf Extract from European Olive (Olea europaea L.) Post-Transcriptionally Suppresses the Epithelial-Mesenchymal Transition and Sensitizes Gastric Cancer Cells to Chemotherapy. Biochemistry Moscow 89, 97–115 (2024). https://doi.org/10.1134/S0006297924010061

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