Im, Ji Hye Kang, Keon Wook Kim, Sun Young Kim, Yoon Gyoon An, Yong Jin Park, Sunghyouk Jeong, Byung Hwa Choi, Song-Yi Lee, Jin-Sun Kang, Keon Wook 2024-01-19T21:31:31Z 2024-01-19T21:31:31Z 2022-01-25 2018-11 0392-9078 https://pubs.kist.re.kr/handle/201004/120713 BackgroundLigand-dependent activation of the G-protein coupled receptor 119 (GPR119) lowers blood glucose via glucose-dependent insulin secretion and intestinal glucagon-like peptide-1 production. However, the function of GPR119 in cancer cells has not been studied.MethodsGPR119 expression was assessed by real-time qPCR and immunohistochemistry in human breast cancer cell lines and breast cancer tissues. Cell proliferation and cell cycle analyses were performed by Incucyte (R) live cell analysis system and flow cutometry, respectively. Autophagy activity was estimeated by western blottings and LC3-GFP transfection.ResultsmRNA or protein expression of GPR119 was detected in 9 cancer cell lines and 19 tissue samples. Cotreatment with GPR119 agonist (MBX-2982 or GSK1292263) significantly potentiated gefitinib-induced cell growth inhibition in gefitinib-insensitive MCF-7 and MDA-MB-231 breast cancer cells. We observed that caspase-3/7 activity was enhanced with the downregulation of Bcl-2 in MCF-7 cells exposed to MBX-2982. Gefitinib-induced autophagy is related with cancer cell survival and chemoresistance. GPR119 agonists inhibit gefitinib-induced autophagosome formation in MCF-7 and MDA-MB-231 cells. MBX-2982 also caused a metabolic shift to enhanced glycolysis accompanied by reduced mitochondrial oxidative phosphorylation. MBX-2982 increased intracellular (2.5mM) and extracellular lactate (20mM) content. Gefitinib-mediated autophagy was suppressed by 20mM lactate in MCF-7 cells.ConclusionsGPR119 agonists reduced mitochondrial OXPHOS and stimulated glycolysis in breast cancer cells, with consequent overproduction of lactate that inhibited autophagosome formation. Because autophagy is crucial for the survival of cancer cells exposed to TKIs, GPR119 agonists potentiated the anticancer effects of TKIs. English BioMed Central GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy Article 10.1186/s13046-018-0949-2 1 Journal of Experimental and Clinical Cancer Research, v.37 Journal of Experimental and Clinical Cancer Research 37 Y scie scopus 000451680700001 2-s2.0-85057519081 Oncology Oncology Article PROTEIN-COUPLED RECEPTOR GROWTH-FACTOR RECEPTOR CHAIN FATTY-ACIDS TARGETED THERAPY CANCER-CELLS GPR81 APOPTOSIS SIGNAL DEATH AMPK Autophagy Breast cancer Gefitinib GPR119 agonist Lactate