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Ageing Research Reviews Jan 2011The insulin/insulin growth factor (IGF) pathway is a critical mediator of longevity and aging. Efforts to extend longevity by altering the insulin/IGF pathway may have... (Review)
Review
The insulin/insulin growth factor (IGF) pathway is a critical mediator of longevity and aging. Efforts to extend longevity by altering the insulin/IGF pathway may have varying effects on other physiological processes. Reduced insulin/IGF levels may decrease the incidence of certain cancers as well as the risk of developing metastatic disease. However, it may also increase the risk of developing cardiovascular disease as well as cardiovascular related mortality. Pursuing the right insulin/IGF pathway targets will require striking a balance between inhibiting cancer cell development and progression and avoiding damage to tissues under normal insulin/IGF-mediated control. This review will discuss the roles of the insulin/IGF pathway in aging and longevity and the development of cancer cell metastasis and considerations in taking insulin/IGF directed targets to the oncology clinic.
Topics: Aging; Animals; Caenorhabditis elegans; Cardiovascular Diseases; Cell Movement; Drosophila melanogaster; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1; Mice; Neoplasms; Signal Transduction; Somatomedins
PubMed: 19896561
DOI: 10.1016/j.arr.2009.10.007 -
Oncotarget Jul 2016Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche... (Review)
Review
Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, proliferation, and drug resistance. As in most cancers, the insulin-like growth factor (IGF) system has been demonstrated to play a key role in the pathogenesis of MM. The IGF system consists of IGF ligands, IGF receptors, IGF binding proteins (IGFBPs), and IGFBP proteases and contributes not only to the survival, proliferation, and homing of MM cells, but also MM-associated angiogenesis and osteolysis. Furthermore, increased IGF-I receptor (IGF-IR) expression on MM cells correlates with a poor prognosis in MM patients. Despite the prominent role of the IGF system in MM, strategies targeting the IGF-IR using blocking antibodies or small molecule inhibitors have failed to translate into the clinic. However, increasing preclinical evidence indicates that IGF-I is also involved in the development of drug resistance against current standard-of-care agents against MM, including proteasome inhibitors, immunomodulatory agents, and corticoids. IGF-IR targeting has been able to overcome or revert this drug resistance in animal models, enhancing the efficacy of standard-of-care agents. This finding has generated renewed interest in the therapeutic potential of IGF-I targeting in MM. The present review provides an update of the impact of the different IGF system components in MM and discusses the diagnostic and therapeutic potentials.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Cell Proliferation; Cell Survival; Clinical Trials as Topic; Drug Resistance, Neoplasm; Endopeptidases; Humans; Insulin; Insulin-Like Growth Factor Binding Proteins; Mice; Molecular Targeted Therapy; Multiple Myeloma; Neoplasm Invasiveness; Neoplasms, Experimental; Neovascularization, Pathologic; Osteolysis; Phosphorylation; Prognosis; Protein Binding; Receptors, Somatomedin; Signal Transduction; Somatomedins
PubMed: 27129151
DOI: 10.18632/oncotarget.8982 -
Molecular Metabolism Jan 2019Recent changes in nutrition and lifestyle have provoked an unprecedented increase in the prevalence of obesity and metabolic disorders. Recognition of the adverse... (Review)
Review
BACKGROUND
Recent changes in nutrition and lifestyle have provoked an unprecedented increase in the prevalence of obesity and metabolic disorders. Recognition of the adverse effects on health has prompted intense efforts to understand the molecular determinants of insulin sensitivity and dysglycemia. In many respects, actions of insulin-like growth factors (IGFs) mirror those of insulin in metabolic regulation. Unlike insulin, however, the bioactivity of IGFs is regulated by a family of seven high-affinity binding proteins (IGFBPs) which confer temporospatial modulation with implications for metabolic homeostasis. In addition, evidence is accumulating that IGF-independent actions of certain of the IGFBPs can directly modulate insulin sensitivity.
SCOPE OF REVIEW
In this review, we discuss the experimental data indicating a critical role for IGF/IGFBP axis in metabolic regulation. We highlight key discoveries through which IGFBPs have emerged as biomarkers or putative therapeutic targets in obesity and diabetes.
MAJOR CONCLUSIONS
Growing evidence suggests that several components of the IGF-IGFBP system could be explored for therapeutic potential in metabolic disorders. Both IGFBP-1 and IGFBP-2 have been favorably linked with insulin sensitivity in humans and preclinical data implicate direct involvement in the molecular regulation of insulin signaling and adiposity respectively. Further studies are warranted to evaluate clinical translation of these findings.
Topics: Diabetes Mellitus; Homeostasis; Humans; Insulin; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Metabolic Diseases; Obesity; Phosphorylation; Protein Transport; Signal Transduction; Somatomedins
PubMed: 30392760
DOI: 10.1016/j.molmet.2018.10.008 -
Endocrinology Dec 2008IGF-I and -II are potent neuronal mitogens and survival factors. The actions of IGF-I and -II are mediated via the type I IGF receptor (IGF-IR) and IGF binding proteins... (Review)
Review
IGF-I and -II are potent neuronal mitogens and survival factors. The actions of IGF-I and -II are mediated via the type I IGF receptor (IGF-IR) and IGF binding proteins regulate the bioavailability of the IGFs. Cell viability correlates with IGF-IR expression and intact IGF-I/IGF-IR signaling pathways, including activation of MAPK/phosphatidylinositol-3 kinase. The expression of IGF-I and -II, IGF-IR, and IGF binding proteins are developmentally regulated in the central and peripheral nervous system. IGF-I therapy demonstrates mixed therapeutic results in the treatment of peripheral nerve injury, neuropathy, and motor neuron diseases such as amyotrophic lateral sclerosis. In this review we discuss the role of IGFs during peripheral nervous system development and the IGF signaling system as the potential therapeutic target for the treatment of nerve injury and motor neuron diseases.
Topics: Animals; Gene Expression; Humans; Insulin-Like Growth Factor Binding Proteins; Models, Biological; Peripheral Nervous System; Receptors, Somatomedin; Signal Transduction; Somatomedins
PubMed: 18719018
DOI: 10.1210/en.2008-1020 -
European Journal of Biochemistry Jul 1990
Review
Topics: Amino Acid Sequence; Animals; Cell Differentiation; Genes; Humans; Insulin-Like Growth Factor I; Molecular Sequence Data; RNA, Messenger; Somatomedins
PubMed: 2197088
DOI: 10.1111/j.1432-1033.1990.tb15595.x -
Journal of Mammary Gland Biology and... Dec 2008The insulin-like growth factors, IGF-I and IGF-II, have endocrine as well as autocrine-paracrine actions on tissue growth. Both IGF ligands are expressed within... (Review)
Review
The insulin-like growth factors, IGF-I and IGF-II, have endocrine as well as autocrine-paracrine actions on tissue growth. Both IGF ligands are expressed within developing mammary tissue throughout postnatal stages with specific sites of expression in the epithelial and stromal compartments. The elucidation of circulating versus local actions and of epithelial versus stromal actions of IGFs in stimulating mammary epithelial development has been the focus of several laboratories. The recent studies addressing IGF ligand function provide support for the hypotheses that (1) the diverse sites of IGF expression may mediate different cellular outcomes, and (2) IGF-I and IGF-II are distinctly regulated and have diverse functions in mammary development. The mechanisms for IGF function likely are mediated, in part, through diverse IGF signaling receptors. The local actions of the IGF ligands and receptors as revealed through recent publications are the focus of this review.
Topics: Animals; Humans; Ligands; Mammary Glands, Animal; Mammary Glands, Human; Receptor Protein-Tyrosine Kinases; Receptors, Somatomedin; Somatomedins
PubMed: 19020961
DOI: 10.1007/s10911-008-9102-8 -
Endocrinology and Metabolism Clinics of... Jun 2012The insulin-like growth factor (IGF) regulatory system is critical for skeletal growth and maintenance. Initially there was great hope that the recombinant IGFs might be... (Review)
Review
The insulin-like growth factor (IGF) regulatory system is critical for skeletal growth and maintenance. Initially there was great hope that the recombinant IGFs might be used clinically for disorders ranging from short stature to fracture repair and osteoporosis. Although this potential was not realized, basic and translational studies have continued, providing significant insights into the role of this family of growth factors in skeletal homeostasis and the pathophysiology of several bone disorders. This article reviews the importance of the IGF regulatory system in skeletal growth and maintenance.
Topics: Animals; Bone Density; Bone Diseases; Bone and Bones; Female; Fractures, Bone; Humans; Insulin-Like Growth Factor Binding Proteins; Male; Mice; Somatomedins; Translational Research, Biomedical
PubMed: 22682633
DOI: 10.1016/j.ecl.2012.04.013 -
Breast Cancer Research : BCR 2002Insulin-like growth factor (IGF)-mediated proliferation and survival are essential for normal development in the mammary gland during puberty and pregnancy. IGFs... (Review)
Review
Insulin-like growth factor (IGF)-mediated proliferation and survival are essential for normal development in the mammary gland during puberty and pregnancy. IGFs interact with IGF-binding proteins and regulate their function. The present review focuses on the role of IGFs and IGF-binding proteins in the mammary gland and describes how modulation of their actions occurs by association with hormones, other growth factors and the extracellular matrix. The review will also highlight the involvement of the IGF axis in breast cancer.
Topics: Animals; Apoptosis; Breast; Breast Neoplasms; Cell Division; Estrogens; Extracellular Matrix; Humans; Insulin-Like Growth Factor Binding Proteins; Matrix Metalloproteinases; Somatomedins
PubMed: 12473169
DOI: 10.1186/bcr535 -
World Journal of Gastroenterology Mar 2016The insulin-like growth factor (IGF) signaling pathway is an important pathway in the process of hepatocarcinogenesis, and the IGF network is clearly dysregulated in... (Review)
Review
The insulin-like growth factor (IGF) signaling pathway is an important pathway in the process of hepatocarcinogenesis, and the IGF network is clearly dysregulated in many cancers and developmental abnormalities. In hepatocellular carcinoma (HCC), only a minority of patients are eligible for curative treatments, such as tumor resection or liver transplant. Unfortunately, there is a high recurrence of HCC after surgical tumor removal. Recent research efforts have focused on targeting IGF axis members in an attempt to find therapeutic options for many health problems. In this review, we shed lights on the regulation of members of the IGF axis, mainly by microRNAs in HCC. MicroRNAs in HCC attempt to halt the aberrant expression of the IGF network, and a single microRNA can have multiple downstream targets in one or more signaling pathways. Targeting microRNAs is a relatively new approach for identifying an efficient radical cure for HCC.
Topics: Animals; Carcinoma, Hepatocellular; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor Binding Proteins; Liver Neoplasms; MicroRNAs; Receptors, Somatomedin; Signal Transduction; Somatomedins
PubMed: 26973407
DOI: 10.3748/wjg.v22.i9.2668 -
Nucleic Acids Research 2004This paper introduces the novel method of contact-based protein sequence alignment, where structural information in the form of contact mutation probabilities is...
This paper introduces the novel method of contact-based protein sequence alignment, where structural information in the form of contact mutation probabilities is incorporated into an alignment routine using contact-mutation matrices (CAO: Contact Accepted mutatiOn). The contact-based alignment routine optimizes the score of matched contacts, which involves four (two per contact) instead of two residues per match in pairwise alignments. The first contact refers to a real side-chain contact in a template sequence with known structure, and the second contact is the equivalent putative contact of a homologous query sequence with unknown structure. An algorithm has been devised to perform a pairwise sequence alignment based on contact information. The contact scores were combined with PAM-type (Point Accepted Mutation) substitution scores after parameterization of gap penalties and score weights by means of a genetic algorithm. We show that owing to the structural information contained in the CAO matrices, significantly improved alignments of distantly related sequences can be obtained. This has allowed us to annotate eight putative Drosophila IGF sequences. Contact-based sequence alignment should therefore prove useful in comparative modelling and fold recognition.
Topics: Algorithms; Amino Acid Sequence; Animals; Drosophila Proteins; Models, Molecular; Molecular Sequence Data; Mutation; Sequence Alignment; Sequence Analysis, Protein; Somatomedins
PubMed: 15121903
DOI: 10.1093/nar/gkh566