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.

Novel Regulators of the IGF System in Cancer

“…Tumor cells metabolize glucose through aerobic glycolysis, rather than oxidative phosphorylation. This metabolic change determines an enhanced need of glucose uptake for ATP synthesis and generation of those metabolic intermediates necessary for biosynthesis of nucleotides, lipids and protein supporting cell proliferation [ 87 , 88 ]. Cancer cells also display metabolic flexibility, which allows the switch from glycolysis to oxidative phosphorylation and vice versa, supporting a role of mitochondria in cancer progression [ 89 ].…”

Microenvironmental Determinants of Breast Cancer Metastasis: Focus on the Crucial Interplay Between Estrogen and Insulin/Insulin-Like Growth Factor Signaling

“…It is worth mentioning that we recently showed that IR-A activation by insulin and IGF-2 plays a role in BC cells metabolic reprogramming by increasing both glycolysis and oxidative phosphorylation. IGF-2–activated IR-A especially enhanced BC cell metabolic flexibility, leading to the acquisition of malignant features consistent with cellular adaptation to a challenging microenvironment characterized by high energy demand ( Vella et al, 2019b ).…”

The IGF-II–Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives

“…A number of subsequent studies have also demonstrated insulin and IGF ligand-specific differences in their activation of the IR A . In particular, such differences have been demonstrated at the gene expression level [10] and at the signaling level [11,12]. In this regard, it is worth noting that IGF-II has been found to be able to bind and transduce signals via both the homo-tetrameric, high-affinity RTKs (IGF1R and IR A ) and via its hetero-tetrameric (IGF1R/IR A ) hybrid receptor in cancer [13].…”

“…In the case of the realization of the importance of the IGF system in cancer, the biological relevance of some of its family components, namely the IGF1R as the supposed sole mediator of the IGF-I and IGF-II effects, came early in the drug industry game, although experimental data related to atypical variants [92,93] and hybrid receptors with its related cousin, the insulin receptor (IR) [94][95][96], were already known. Indeed, the overexpression of the IR in cancer, first reported in breast tumors and related cell lines [97,98], has not been interpreted as relevant by the supporters of the "IGF1R mandatory-transducer" hypothesis, based on the assumption that the IR serves solely as a purely metabolic transducer, of which overexpression in cancer cells merely provides metabolic advantages over normal tissues with regards to nutrient consumption [12]. This scenario, reproducible but incomplete, began to be revealed as a fallacy when the short isoform of the IR (not expressing its exon 11 on the extracellular domain) was shown to be an onco-fetal high-IGF-II-affinity receptor.…”