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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Cagla Tekin¹, Melis Ercelik¹, Pavel Dunaev², Aigul Galembikova², Gulcin Tezcan³, Secil Ak Aksoy^4,5, Ferah Budak⁶, Ozgen Isık⁷, Nesrin Ugras⁸, Sergei Boichuk^2,9,10,a*, and Berrin Tunca^1,b*

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

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

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

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

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

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

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

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

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

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

Received October 10, 2023; Revised November 21, 2023; Accepted November 30, 2023

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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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KEY WORDS: gastric cancer, Olea europaea leaf extract, epithelial-mesenchymal transition, apoptosis, chemotherapeutic agents, cadherin 2, SOX2, non-coding RNA, miR-23b-3p, anti-cancer effect

DOI: 10.1134/S0006297924010061

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