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INVESTIGATION OF THE EFFECTS OF METFORMIN ON THE miR-21/PTEN/Akt PATHWAY IN HT-29 HUMAN COLORECTAL ADENOCARCINOMA CELL AND HUVEC CO-CULTURE

CIGDEM SEVIM 1*, ALI TAGHIZADEHGHALEHJOUGHI 2, MEHTAP KARA 3, ALEXANDER E. NOSYREV 4, GEORGE MIHAI NIȚULESCU 5, DENISA MARGINĂ 6, ARISTIDES TSATSAKIS 7

1Deparment of Medical Pharmacology, Faculty of Medicine, University of Kastamonu, 37200, Kastamonu, Turkey
2 Deparment of Medical Pharmacology, Faculty of Medicine, University of Bilecik Şeyh Edebali, 11230, Bilecik, Turkey
3 Deparment of Pharmaceutical Toxicology, Faculty of Pharmacy,University of Istanbul, 34116, Istanbul, Turkey
4 Center of Bioanalytical Research and Molecular Design, Sechenov First Moscow State Medical University, 119991 Moscow, Russian Federation
5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956, Bucharest, Romania
6 Department of Biochemistry, Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956, Bucharest, Romania
7 Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003, Heraklion, Greece

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Colon adenocarcinoma is a major cause of cancer mortality worldwide. Type 2 diabetic people have an increased risk of developing colorectal cancer compared with nondiabetic people. There are studies showing that metformin inhibits angiogenesis, which is an important stage in cancer metastasis. Our aim was to identify the effects of metformin on miR-21, PTEN, and Akt gene expressions associated with angiogenesis in co‐culture conditions established with human colorectal adenocarcinoma cells (HT-29) and human umbilical vein endothelial (HUVEC) cells. Cytotoxicity was evaluated via MTT assay, and PTEN, Akt, and miR-21 expressions were measured by real-time polymerase chain reaction in HUVEC cells under the effects of HT29 cells. Cell viability decreased with increasing doses of metformin, especially in the 160 μg/mL metformin treatment group. According to real-time PCR results, PTEN was significantly upregulated in 80 and 160 μg/mL metformin- treated cells, and Akt, and miR-21 expressions were downregulated significantly in all metformin treatment groups. An inverse relation was found between PTEN, Akt and miR-21 levels in HUVEC cells under HT29-HUVEC co-culture conditions. Increased PTEN signalling was associated with the prevention of angiogenesis through reducing cell proliferation and migration. The miR‐21/PTEN/Akt signalling pathway may have a crucial role in the molecular mechanism of metformin's antiangiogenic effect.