Emerging Paradigms of Insulin-Like Activities: From Pathophysiology to Targeted Therapy in Cancer and Diabetes

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (20 June 2019) | Viewed by 56930

Special Issue Editor


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Guest Editor
1. Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, 17164 Stockholm, Sweden
2. Karolinska University Hospital, Solna, Sweden
Interests: signaling; RTK; GPCR; ubiquitination; cancer; arrestin; GRK; IGF-1R; targeted therapy insulin; Insulin/IGF axis; metabolic syndrome; molecular pathology
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Special Issue Information

Dear Colleagues,

In modern society, escalating levels of obesity parallel increasing rates of diabetes, cardiovascular disease, and cancer, raising legitimate questions regarding overlapping pathogenesis. For instance, it is well recognized that insulin resistance is likely to be a significant link between obesity, diabetes, and cancer (ODC). Several determinants, including lifestyle and genetic factors, have been shown to support ODC pathogeny. Nevertheless, it is generally accepted that cell signaling anomalies play a dominant role in the development of each ODC entity. These abnormal signals are often initiated or sustained by plasma membrane receptors, such as tyrosine–kinase receptors (RTK) or G protein-coupled receptors (GPCRs). Although different receptor families can utilize common intracellular signaling proteins and pathways, each cell surface receptor family leads to specific biological outcomes within the cell. Multilayered crosstalk between different receptor families governs the coordination of downstream signaling molecules, and therefore the concluding effectors—directing the development and maintenance of the ODC phenotype. Rigorous control of the cells’ signaling network entails feedback and feedforward loops, which orchestrate the resultant biological effects. Such regulatory mechanisms involve receptor-internalization machinery, scaffolding of signaling complexes, post-translational modifications, as well as transcriptional control of signaling molecules. Recently added to this complex system, noncoding RNAs (ncRNA) are now recognized as critical regulators, as well as regulation targets, of cellular signaling.

Among RTKs, the insulin receptor family (IIGF-1R), including the insulin receptor (IR) and insulin-like growth factor type-1 receptor (IGF-1R), are the most important players in ODC.

Today, controlling the IIGF-IR and components of their downstream pathways in different pathological contexts is a major research area. This Special Issue of Cells will follow the development of our understanding of IIGF-1R family signaling, through the design of different IIGF-1R targeting strategies and consideration of appropriate models, with a particular focus on those relating to cancer and diabetes.

Dr. Leonard Girnita
Guest Editor

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Keywords

  • RTK
  • GPCR
  • ubiquitination
  • signaling
  • cancer
  • metabolic syndrom
  • diabetes
  • IGF-1R
  • targeted therapy
  • insulin

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Published Papers (9 papers)

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Research

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19 pages, 2830 KiB  
Article
IGF-1 Signalling Regulates Mitochondria Dynamics and Turnover through a Conserved GSK-3β–Nrf2–BNIP3 Pathway
by Sarah Riis, Joss B. Murray and Rosemary O’Connor
Cells 2020, 9(1), 147; https://doi.org/10.3390/cells9010147 - 8 Jan 2020
Cited by 55 | Viewed by 6029
Abstract
The Insulin-like Growth Factor I (IGF-1) signalling pathway is essential for cell growth and facilitates tumourogenic processes. We recently reported that IGF-1 induces a transcriptional programme for mitochondrial biogenesis, while also inducing expression of the mitophagy receptor BCL2/adenovirus E1B 19 kDa protein-interacting protein [...] Read more.
The Insulin-like Growth Factor I (IGF-1) signalling pathway is essential for cell growth and facilitates tumourogenic processes. We recently reported that IGF-1 induces a transcriptional programme for mitochondrial biogenesis, while also inducing expression of the mitophagy receptor BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), suggesting that IGF-1 has a key mitochondria-protective role in cancer cells. Here, we investigated this further and delineated the signaling pathway for BNIP3 induction. We established that IGF-1 induced BNIP3 expression through a known AKT serine/threonine kinase 1 (AKT)-mediated inhibitory phosphorylation on Glycogen Synthase Kinase-3β (GSK-3β), leading to activation of Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2/Nrf2) and acting through the downstream transcriptional regulators Nuclear Respiratory Factor-1 (NRF1) and Hypoxia-inducible Factor 1 subunit α (HIF-1α). Suppression of IGF-1 signaling, Nrf2 or BNIP3 caused the accumulation of elongated mitochondria and altered the mitochondrial dynamics. IGF-1R null Mouse Embryonic Fibroblasts (MEFs) were impaired in the BNIP3 expression and in the capacity to mount a cell survival response in response to serum deprivation or mitochondrial stress. IGF-1 signalling enhanced the cellular capacity to induce autophagosomal turnover in response to activation of either general autophagy or mitophagy. Overall, we conclude that IGF-1 mediated a mitochondria-protective signal that was coordinated through the cytoprotective transcription factor Nrf2. This pathway coupled mitochondrial biogenesis with BNIP3 induction, and increased the cellular capacity for autophagosome turnover, whilst enhancing survival under conditions of metabolic or mitochondrial stress. Full article
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15 pages, 2810 KiB  
Article
Sex Differences in High Fat Diet-Induced Metabolic Alterations Correlate with Changes in the Modulation of GRK2 Levels
by Alba C. Arcones, Marta Cruces-Sande, Paula Ramos, Federico Mayor and Cristina Murga
Cells 2019, 8(11), 1464; https://doi.org/10.3390/cells8111464 - 19 Nov 2019
Cited by 17 | Viewed by 6538
Abstract
A differential sex-related sensitivity has been reported in obesity and insulin resistance-related cardio-metabolic diseases, with a lower incidence of these pathologies being observed in young females when compared to age-matched males. However, such relative protection is lost with age. The mechanisms underlying such [...] Read more.
A differential sex-related sensitivity has been reported in obesity and insulin resistance-related cardio-metabolic diseases, with a lower incidence of these pathologies being observed in young females when compared to age-matched males. However, such relative protection is lost with age. The mechanisms underlying such sex and age-related changes in the susceptibility to diabetes and obesity are not fully understood. Herein, we report that the relative protection that is displayed by young female mice, as compared to male littermates, against some of the metabolic alterations that are induced by feeding a high fat diet (HFD), correlates with a lower upregulation of the protein levels of G protein-coupled receptor kinase (GRK2), which is a key regulator of both insulin and G protein-coupled receptor signaling, in the liver and adipose tissue. Interestingly, when the HFD is initiated in middle-aged (32 weeks) female mice, these animals are no longer protected and display a more overt obese and insulin-resistant phenotype, along with a more evident increase in the GRK2 protein levels in metabolically relevant tissues in such conditions. Our data suggest that GRK2 dosage might be involved in the sex and age-biased sensitivity to insulin resistance-related pathologies. Full article
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26 pages, 4546 KiB  
Article
Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation
by Veronica Vella, Maria Luisa Nicolosi, Marika Giuliano, Andrea Morrione, Roberta Malaguarnera and Antonino Belfiore
Cells 2019, 8(9), 1017; https://doi.org/10.3390/cells8091017 - 1 Sep 2019
Cited by 26 | Viewed by 3980
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 [...] Read more.
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. Full article
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Review

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16 pages, 1566 KiB  
Review
Non-Coding RNAs in IGF-1R Signaling Regulation: The Underlying Pathophysiological Link between Diabetes and Cancer
by Baoqing Chen, Junyan Li, Dongmei Chi, Iman Sahnoune, Steliana Calin, Leonard Girnita and George A. Calin
Cells 2019, 8(12), 1638; https://doi.org/10.3390/cells8121638 - 14 Dec 2019
Cited by 30 | Viewed by 5570
Abstract
The intricate molecular network shared between diabetes mellitus (DM) and cancer has been broadly understood. DM has been associated with several hormone-dependent malignancies, including breast, pancreatic, and colorectal cancer (CRC). Insulin resistance, hyperglycemia, and inflammation are the main pathophysiological mechanisms linking DM to [...] Read more.
The intricate molecular network shared between diabetes mellitus (DM) and cancer has been broadly understood. DM has been associated with several hormone-dependent malignancies, including breast, pancreatic, and colorectal cancer (CRC). Insulin resistance, hyperglycemia, and inflammation are the main pathophysiological mechanisms linking DM to cancer. Non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are widely appreciated as pervasive regulators of gene expression, governing the evolution of metabolic disorders, including DM and cancer. The ways ncRNAs affect the development of DM complicated with cancer have only started to be revealed in recent years. Insulin-like growth factor 1 receptor (IGF-1R) signaling is a master regulator of pathophysiological processes directing DM and cancer. In this review, we briefly summarize a number of well-known miRNAs and lncRNAs that regulate the IGF-1R in DM and cancer, respectively, and further discuss the potential underlying molecular pathogenesis of this disease association. Full article
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23 pages, 5640 KiB  
Review
Below the Surface: IGF-1R Therapeutic Targeting and Its Endocytic Journey
by Caitrin Crudden, Dawei Song, Sonia Cismas, Eric Trocmé, Sylvya Pasca, George A. Calin, Ada Girnita and Leonard Girnita
Cells 2019, 8(10), 1223; https://doi.org/10.3390/cells8101223 - 9 Oct 2019
Cited by 30 | Viewed by 6000
Abstract
Ligand-activated plasma membrane receptors follow pathways of endocytosis through the endosomal sorting apparatus. Receptors cluster in clathrin-coated pits that bud inwards and enter the cell as clathrin-coated vesicles. These vesicles travel through the acidic endosome whereby receptors and ligands are sorted to be [...] Read more.
Ligand-activated plasma membrane receptors follow pathways of endocytosis through the endosomal sorting apparatus. Receptors cluster in clathrin-coated pits that bud inwards and enter the cell as clathrin-coated vesicles. These vesicles travel through the acidic endosome whereby receptors and ligands are sorted to be either recycled or degraded. The traditional paradigm postulated that the endocytosis role lay in signal termination through the removal of the receptor from the cell surface. It is now becoming clear that the internalization process governs more than receptor signal cessation and instead reigns over the entire spatial and temporal wiring of receptor signaling. Governing the localization, the post-translational modifications, and the scaffolding of receptors and downstream signal components established the endosomal platform as the master regulator of receptor function. Confinement of components within or between distinct organelles means that the endosome instructs the cell on how to interpret and translate the signal emanating from any given receptor complex into biological effects. This review explores this emerging paradigm with respect to the cancer-relevant insulin-like growth factor type 1 receptor (IGF-1R) and discusses how this perspective could inform future targeting strategies. Full article
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32 pages, 1728 KiB  
Review
The Neglected Insulin: IGF-II, a Metabolic Regulator with Implications for Diabetes, Obesity, and Cancer
by Jeff M. P. Holly, Kalina Biernacka and Claire M. Perks
Cells 2019, 8(10), 1207; https://doi.org/10.3390/cells8101207 - 6 Oct 2019
Cited by 49 | Viewed by 5842
Abstract
When originally discovered, one of the initial observations was that, when all of the insulin peptide was depleted from serum, the vast majority of the insulin activity remained and this was due to a single additional peptide, IGF-II. The IGF-II gene is adjacent [...] Read more.
When originally discovered, one of the initial observations was that, when all of the insulin peptide was depleted from serum, the vast majority of the insulin activity remained and this was due to a single additional peptide, IGF-II. The IGF-II gene is adjacent to the insulin gene, which is a result of gene duplication, but has evolved to be considerably more complicated. It was one of the first genes recognised to be imprinted and expressed in a parent-of-origin specific manner. The gene codes for IGF-II mRNA, but, in addition, also codes for antisense RNA, long non-coding RNA, and several micro RNA. Recent evidence suggests that each of these have important independent roles in metabolic regulation. It has also become clear that an alternatively spliced form of the insulin receptor may be the principle IGF-II receptor. These recent discoveries have important implications for metabolic disorders and also for cancer, for which there is renewed acknowledgement of the importance of metabolic reprogramming. Full article
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15 pages, 736 KiB  
Review
IGF2/IGF1R Signaling as a Therapeutic Target in MYB-Positive Adenoid Cystic Carcinomas and Other Fusion Gene-Driven Tumors
by Mattias K. Andersson, Pierre Åman and Göran Stenman
Cells 2019, 8(8), 913; https://doi.org/10.3390/cells8080913 - 16 Aug 2019
Cited by 32 | Viewed by 5408
Abstract
Chromosome rearrangements resulting in pathogenetically important gene fusions are a common feature of many cancers. They are often potent oncogenic drivers and have key functions in central cellular processes and pathways and encode transcription factors, transcriptional co-regulators, growth factor receptors, tyrosine kinases, and [...] Read more.
Chromosome rearrangements resulting in pathogenetically important gene fusions are a common feature of many cancers. They are often potent oncogenic drivers and have key functions in central cellular processes and pathways and encode transcription factors, transcriptional co-regulators, growth factor receptors, tyrosine kinases, and chromatin modifiers. In addition to being useful diagnostic biomarkers, they are also targets for development of new molecularly targeted therapies. Studies in recent decades have shown that several oncogenic gene fusions interact with the insulin-like growth factor (IGF) signaling pathway. For example, the MYB–NFIB fusion in adenoid cystic carcinoma is regulated by IGF1R through an autocrine loop, and IGF1R is a downstream target of the EWSR1–WT1 and PAX3–FKHR fusions in desmoplastic small round cell tumors and alveolar rhabdomyosarcoma, respectively. Here, we will discuss the mechanisms behind the interactions between oncogenic gene fusions and the IGF signaling pathway. We will also discuss the role of therapeutic inhibition of IGF1R in fusion gene driven malignancies. Full article
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25 pages, 776 KiB  
Review
Therapeutic Targeting of the IGF Axis
by Eliot Osher and Valentine M. Macaulay
Cells 2019, 8(8), 895; https://doi.org/10.3390/cells8080895 - 14 Aug 2019
Cited by 112 | Viewed by 7997
Abstract
The insulin like growth factor (IGF) axis plays a fundamental role in normal growth and development, and when deregulated makes an important contribution to disease. Here, we review the functions mediated by ligand-induced IGF axis activation, and discuss the evidence for the involvement [...] Read more.
The insulin like growth factor (IGF) axis plays a fundamental role in normal growth and development, and when deregulated makes an important contribution to disease. Here, we review the functions mediated by ligand-induced IGF axis activation, and discuss the evidence for the involvement of IGF signaling in the pathogenesis of cancer, endocrine disorders including acromegaly, diabetes and thyroid eye disease, skin diseases such as acne and psoriasis, and the frailty that accompanies aging. We discuss the use of IGF axis inhibitors, focusing on the different approaches that have been taken to develop effective and tolerable ways to block this important signaling pathway. We outline the advantages and disadvantages of each approach, and discuss progress in evaluating these agents, including factors that contributed to the failure of many of these novel therapeutics in early phase cancer trials. Finally, we summarize grounds for cautious optimism for ongoing and future studies of IGF blockade in cancer and non-malignant disorders including thyroid eye disease and aging. Full article
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15 pages, 3785 KiB  
Review
Genome-Wide Profiling of Laron Syndrome Patients Identifies Novel Cancer Protection Pathways
by Haim Werner, Lena Lapkina-Gendler, Laris Achlaug, Karthik Nagaraj, Lina Somri, Danielle Yaron-Saminsky, Metsada Pasmanik-Chor, Rive Sarfstein, Zvi Laron and Shoshana Yakar
Cells 2019, 8(6), 596; https://doi.org/10.3390/cells8060596 - 15 Jun 2019
Cited by 34 | Viewed by 8827
Abstract
Laron syndrome (LS), or primary growth hormone resistance, is a prototypical congenital insulin-like growth factor 1 (IGF1) deficiency. The recent epidemiological finding that LS patients do not develop cancer is of major scientific and clinical relevance. Epidemiological data suggest that congenital IGF1 deficiency [...] Read more.
Laron syndrome (LS), or primary growth hormone resistance, is a prototypical congenital insulin-like growth factor 1 (IGF1) deficiency. The recent epidemiological finding that LS patients do not develop cancer is of major scientific and clinical relevance. Epidemiological data suggest that congenital IGF1 deficiency confers protection against the development of malignancies. This ‘experiment of nature’ reflects the critical role of IGF1 in tumor biology. The present review article provides an overview of recently conducted genome-wide profiling analyses aimed at identifying mechanisms and signaling pathways that are directly responsible for the link between life-time low IGF1 levels and protection from tumor development. The review underscores the concept that ‘data mining’ an orphan disease might translate into new developments in oncology. Full article
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