Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation.

Abstract

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 IGF1R-ablated MCF7 (MCF7IGF1R-ve) 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 MCF7IGF1R-ve/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.

• Authors: Veronica Vella, Maria Luisa Nicolosi, Marika Giuliano, Andrea Morrione, Roberta Malaguarnera, Antonino Belfiore
• Journal: Cells (Cells) Vol. 8 Issue 9 (09 01 2019) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 31480557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites
• IGF1R protein, human
• IGF2 protein, human
• Insulin
• Protein Isoforms
• Insulin-Like Growth Factor II
• Metformin
• Deoxyglucose
• Receptor, IGF Type 1

Topics

• Antimetabolites (pharmacology)
• Breast Neoplasms (metabolism)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Deoxyglucose (pharmacology)
• Female
• Glycolysis
• Humans
• Insulin (metabolism)
• Insulin-Like Growth Factor II (metabolism)
• MCF-7 Cells
• Metformin (pharmacology)
• Mitochondria (drug effects, metabolism)
• Protein Isoforms (genetics, metabolism)
• Receptor, IGF Type 1 (genetics, metabolism)