GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy
Abstract Background Ligand-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. Methods GPR119 expressi...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-11-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-0949-2 |
| _version_ | 1811207339961745408 |
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| author | Ji Hye Im Keon Wook Kang Sun Young Kim Yoon Gyoon Kim Yong Jin An Sunghyouk Park Byung Hwa Jeong Song-Yi Choi Jin-Sun Lee Keon Wook Kang |
| author_facet | Ji Hye Im Keon Wook Kang Sun Young Kim Yoon Gyoon Kim Yong Jin An Sunghyouk Park Byung Hwa Jeong Song-Yi Choi Jin-Sun Lee Keon Wook Kang |
| author_sort | Ji Hye Im |
| collection | DOAJ |
| description | Abstract Background Ligand-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. Methods GPR119 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® live cell analysis system and flow cutometry, respectively. Autophagy activity was estimeated by western blottings and LC3-GFP transfection. Results mRNA 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 (~ 2.5 mM) and extracellular lactate (~ 20 mM) content. Gefitinib-mediated autophagy was suppressed by 20 mM lactate in MCF-7 cells. Conclusions GPR119 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. |
| first_indexed | 2024-04-12T04:01:22Z |
| format | Article |
| id | doaj.art-14a1c65bc9e04558abe847f7d32fcdb1 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-12T04:01:22Z |
| publishDate | 2018-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-14a1c65bc9e04558abe847f7d32fcdb12022-12-22T03:48:42ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-11-0137111510.1186/s13046-018-0949-2GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagyJi Hye Im0Keon Wook Kang1Sun Young Kim2Yoon Gyoon Kim3Yong Jin An4Sunghyouk Park5Byung Hwa Jeong6Song-Yi Choi7Jin-Sun Lee8Keon Wook Kang9College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National UniversityDepartment of Nuclear Medicine, College of Medicine, Seoul National UniversityCollege of Pharmacy, Dankook UniversityCollege of Pharmacy, Dankook UniversityNatural Product Research Institute, College of Pharmacy, Seoul National UniversityNatural Product Research Institute, College of Pharmacy, Seoul National UniversityMolecular Recognition Research Center, Korea Institute of Science and TechnologyCollege of Medicine, Chungnam National UniversityCollege of Medicine, Chungnam National UniversityCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National UniversityAbstract Background Ligand-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. Methods GPR119 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® live cell analysis system and flow cutometry, respectively. Autophagy activity was estimeated by western blottings and LC3-GFP transfection. Results mRNA 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 (~ 2.5 mM) and extracellular lactate (~ 20 mM) content. Gefitinib-mediated autophagy was suppressed by 20 mM lactate in MCF-7 cells. Conclusions GPR119 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.http://link.springer.com/article/10.1186/s13046-018-0949-2AutophagyBreast cancerGefitinibGPR119 agonistLactate |
| spellingShingle | Ji Hye Im Keon Wook Kang Sun Young Kim Yoon Gyoon Kim Yong Jin An Sunghyouk Park Byung Hwa Jeong Song-Yi Choi Jin-Sun Lee Keon Wook Kang GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy Journal of Experimental & Clinical Cancer Research Autophagy Breast cancer Gefitinib GPR119 agonist Lactate |
| title | GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy |
| title_full | GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy |
| title_fullStr | GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy |
| title_full_unstemmed | GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy |
| title_short | GPR119 agonist enhances gefitinib responsiveness through lactate-mediated inhibition of autophagy |
| title_sort | gpr119 agonist enhances gefitinib responsiveness through lactate mediated inhibition of autophagy |
| topic | Autophagy Breast cancer Gefitinib GPR119 agonist Lactate |
| url | http://link.springer.com/article/10.1186/s13046-018-0949-2 |
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