Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation
Previously published work has demonstrated that overexpression of the insulin receptor isoform A (IR-A) might play a role in cancer progression and metastasis. The IR has a predominant metabolic role in physiology, but the potential role of IR-A in cancer metabolic reprogramming is unknown. We aimed...
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MDPI AG
2019-09-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/9/1017 |
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| author | Veronica Vella Maria Luisa Nicolosi Marika Giuliano Andrea Morrione Roberta Malaguarnera Antonino Belfiore |
| author_facet | Veronica Vella Maria Luisa Nicolosi Marika Giuliano Andrea Morrione Roberta Malaguarnera Antonino Belfiore |
| author_sort | Veronica Vella |
| collection | DOAJ |
| description | Previously published work has demonstrated that overexpression of the insulin receptor isoform A (IR-A) might play a role in cancer progression and metastasis. The IR has a predominant metabolic role in physiology, but the potential role of IR-A in cancer metabolic reprogramming is unknown. We aimed to characterize the metabolic impact of IR-A and its ligand insulin like growth factor 2 (IGF2) in human breast cancer (BC) cells. To establish autocrine IGF2 action, we generated human BC cells MCF7 overexpressing the human IGF2, while we focused on the metabolic effect of IR-A by stably infecting <i>IGF1R</i>-ablated MCF7 (MCF7<i><sup>IGF1R</sup></i><sup>-ve</sup>) cells with a human IR-A cDNA. We then evaluated the expression of key metabolism related molecules and measured real-time extracellular acidification rates and oxygen consumption rates using the Seahorse technology. MCF7/IGF2 cells showed increased proliferation and invasion associated with aerobic glycolysis and mitochondrial biogenesis and activity. In MCF7<i><sup>IGF1R</sup></i><sup>-ve</sup>/IR-A cells insulin and IGF2 stimulated similar metabolic changes and were equipotent in eliciting proliferative responses, while IGF2 more potently induced invasion. The combined treatment with the glycolysis inhibitor 2-deoxyglucose (2DG) and the mitochondrial inhibitor metformin blocked cell invasion and colony formation with additive effects. Overall, these results indicate that IGF2 and IR-A overexpression may contribute to BC metabolic reprogramming. |
| first_indexed | 2024-03-12T09:56:28Z |
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| id | doaj.art-73719973512f42da8505e278fdead9d1 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T09:56:28Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-73719973512f42da8505e278fdead9d12023-09-02T12:10:01ZengMDPI AGCells2073-44092019-09-0189101710.3390/cells8091017cells8091017Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin StimulationVeronica Vella0Maria Luisa Nicolosi1Marika Giuliano2Andrea Morrione3Roberta Malaguarnera4Antonino Belfiore5Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, ItalyEndocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, ItalyEndocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, ItalyDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USASchool of Human and Social Sciences, “Kore” University of Enna, 94100 Enna, ItalyEndocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, ItalyPreviously published work has demonstrated that overexpression of the insulin receptor isoform A (IR-A) might play a role in cancer progression and metastasis. The IR has a predominant metabolic role in physiology, but the potential role of IR-A in cancer metabolic reprogramming is unknown. We aimed to characterize the metabolic impact of IR-A and its ligand insulin like growth factor 2 (IGF2) in human breast cancer (BC) cells. To establish autocrine IGF2 action, we generated human BC cells MCF7 overexpressing the human IGF2, while we focused on the metabolic effect of IR-A by stably infecting <i>IGF1R</i>-ablated MCF7 (MCF7<i><sup>IGF1R</sup></i><sup>-ve</sup>) cells with a human IR-A cDNA. We then evaluated the expression of key metabolism related molecules and measured real-time extracellular acidification rates and oxygen consumption rates using the Seahorse technology. MCF7/IGF2 cells showed increased proliferation and invasion associated with aerobic glycolysis and mitochondrial biogenesis and activity. In MCF7<i><sup>IGF1R</sup></i><sup>-ve</sup>/IR-A cells insulin and IGF2 stimulated similar metabolic changes and were equipotent in eliciting proliferative responses, while IGF2 more potently induced invasion. The combined treatment with the glycolysis inhibitor 2-deoxyglucose (2DG) and the mitochondrial inhibitor metformin blocked cell invasion and colony formation with additive effects. Overall, these results indicate that IGF2 and IR-A overexpression may contribute to BC metabolic reprogramming.https://www.mdpi.com/2073-4409/8/9/1017insulin receptor isoform AIGF2IGF1Rmetabolic reprogrammingaerobic glycolysismetabolic flexibilitybreast cancer |
| spellingShingle | Veronica Vella Maria Luisa Nicolosi Marika Giuliano Andrea Morrione Roberta Malaguarnera Antonino Belfiore Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation Cells insulin receptor isoform A IGF2 IGF1R metabolic reprogramming aerobic glycolysis metabolic flexibility breast cancer |
| title | Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation |
| title_full | Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation |
| title_fullStr | Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation |
| title_full_unstemmed | Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation |
| title_short | Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation |
| title_sort | insulin receptor isoform a modulates metabolic reprogramming of breast cancer cells in response to igf2 and insulin stimulation |
| topic | insulin receptor isoform A IGF2 IGF1R metabolic reprogramming aerobic glycolysis metabolic flexibility breast cancer |
| url | https://www.mdpi.com/2073-4409/8/9/1017 |
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