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OBJECTIVE To investigate the effect of metformin (MET) on enhancing the sensitivity of human pancreatic cancer cells to gemcitabine (GEM) by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. MATERIALS AND METHODS The GEM-resistant human pancreatic cancer PANC-1/GEM cell line was established, and the proliferation ability of PANC-1 and PANC-1/GEM cell lines was detected using the Cell Counting Kit-8 (CCK-8), which was then detected by flow cytometry after they were labeled by Ki67. Quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and Western blotting were adopted to detect the difference in the mTOR expression between PANC-1 and PANC-1/GEM cell lines. The proliferation ability of PANC-1/GEM/MET and PANC-1/GEM cell lines was determined using CCK-8 after drug-resistant cell lines were treated with 20 mmol/L MET combined with 0.4 μmol/L GEM or 0.4 μmol/L GEM alone for 48 h. Colony formation assay was applied to detect the proliferation ability of cells. The difference in the expression of mTOR/PI3K/Akt between PANC-1/GEM/MET and PANC-1/GEM cell lines was tested via qRT-PCR and Western blotting, respectively. RESULTS Compared with PANC-1 cells, PANC-1/GEM cells had significantly enhanced proliferation ability (p<0.01). Flow cytometry results showed that the proliferation ability of PANC-1/GEM cells was notably enhanced (p<0.01). The expression level and phosphorylation level of mTOR in drug-resistant cell lines were increased (p<0.01). After the drug-resistant cell lines were treated with 20 mmol/L MET for 48 h, the proliferation ability of PANC-1/GEM/MET cells was evidently decreased compared with that of PANC-1/GEM cells (p<0.01). The messenger ribonucleic acid (mRNA) and protein expression levels of mTOR/PI3K/Akt were markedly down-regulated (p<0.01). CONCLUSIONS MET can regulate the PI3K/Akt/mTOR signaling pathway to enhance the sensitivity of human pancreatic cancer cells to GEM.