Insulin-like Growth Factor Family Research Articles

Plasma IGFBP-3 and IGFBP-5 levels are decreased during acute manic episodes in bipolar disorder patients.

Introduction: Bipolar disorder (BD) is a recurrent and disabling psychiatric disorder related to low-grade peripheral inflammation and altered levels of the members of the insulin-like growth factor (IGF) family. The aim of this study was to evaluate the plasma levels of IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, IGFBP-5, IGFBP-7, and inflammatory markers such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1β (MIP-1β). Methods: We used the Young Mania Rating Scale (YMRS) to determine the severity of the symptomatology, while proteins were measured by enzyme-linked immunosorbent assay (ELISA). We included 20 patients with BD who suffered a manic episode and 20 controls. Some BD patients (n = 10) were evaluated after a period (17 ± 8days) of pharmacological treatment. Results: No statistical difference was found in IGF-2, IGFBP-1, IGFBP-7, TNF-α, and MIP-1β levels. However, IGFBP-3 and IGFBP-5 levels were found to be statistically decreased in BD patients. Conversely, the MCP-1 level was significantly increased in BD patients, but their levels were normalized after treatment. Intriguingly, only IGFBP-1 levels were significantly decreased after treatment. No significant correlation was found between the YMRS and any of the proteins studied either before or after treatment or between IGF proteins and inflammatory markers. Discussion: To some extent, IGFBP-3 and IGFBP-5 might be further explored as potential indicators of treatment responsiveness or diagnosis biomarkers in BD.

Identification of Insulin-like Growth Factor (IGF) Family Genes in the Golden Pompano, Trachinotus ovatus: Molecular Cloning, Characterization and Gene Expression.

Insulin-like growth factors (IGFs) are hormones that primarily stimulate and regulate animal physiological processes. In this study, we cloned and identified the open reading frame (ORF) cDNA sequences of IGF family genes: the insulin-like growth factor 1 (IGF1), insulin-like growth factor 2 (IGF2), and insulin-like growth factor 3 (IGF3). We found that IGF1, IGF2, and IGF3 have a total length of 558, 648, and 585 base pairs (bp), which encoded a predicted protein with 185, 215, and 194 amino acids (aa), respectively. Multiple sequences and phylogenetic tree analysis showed that the mature golden pompano IGFs had been conserved and showed high similarities with other teleosts. The tissue distribution experiment showed that IGF1 and IGF2 mRNA levels were highly expressed in the liver of female and male fish. In contrast, IGF3 was highly expressed in the gonads and livers of male and female fish, suggesting a high influence on fish reproduction. The effect of fasting showed that IGF1 and mRNA expression had no significant difference in the liver but significantly decreased after long-term (7 days) fasting in the muscles and started to recover after refeeding. IGF2 mRNA expression showed no significant difference in the liver but had a significant difference in muscles for short-term (2 days) and long-term fasting, which started to recover after refeeding, suggesting muscles are more susceptible to both short-term and long-term fasting. In vitro incubation of 17β-estradiol (E2) was observed to decrease the IGF1 and IGF3 mRNA expression level in a dose- (0.1, 1, and 10 μM) and time- (3, 6, and 12 h) dependent manner. In addition, E2 had no effect on IGF2 mRNA expression levels in a time- and dose-dependent manner. The effect of 17α-methyltestosterone (MT) in vitro incubation was observed to significantly increase the IGF3 mRNA expression level in a time- and dose-dependent manner. MT had no effect on IGF2 mRNA but was observed to decrease the IGF1 mRNA expression in the liver. Taken together, these data indicate that E2 and MT may either increase or decrease IGF expression in fish; this study provides basic knowledge and understanding of the expression and regulation of IGF family genes in relation to the nutritional status, somatic growth, and reproductive endocrinology of golden pompano for aquaculture development.

Insulin-like growth factor family and prostate cancer: new insights and emerging opportunities.

Prostate cancer is the second most commonly diagnosed cancer in men. The mammalian insulin-like growth factor (IGF) family is made up of three ligands (IGF-I, IGF-II, and insulin), three receptors (IGF-I receptor (IGF-1R), insulin receptor (IR), and IGF-II receptor (IGF-2R)), and six IGF-binding proteins (IGFBPs). IGF-I and IGF-II were identified as potent mitogens and were previously associated with an increased risk of cancer development including prostate cancer. Several reports showed controversy about the expression of the IGF family and their connection to prostate cancer risk due to the high degree of heterogeneity among prostate tumors, sampling bias, and evaluation techniques. Despite that, it is clear that several IGF family members play a role in prostate cancer development, metastasis, and androgen-independent progression. In this review, we aim to expand our understanding of prostate tumorigenesis and regulation through the IGF system. Further understanding of the role of IGF signaling in PCa shows promise and needs to be considered in the context of a comprehensive treatment strategy.

Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation.

Atrial fibrillation (AF) is one of the most common persistent arrhythmias among adult cardiovascular diseases. It is important to identify potential risk factors for AF. Members of the insulin-like growth factor (IGF) family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases, and previous population-based studies indicate associations between IGF family members and AF. However, the causal effects of IGF family members in AF have not been evaluated. In the current study two-sample Mendelian Randomization (MR) was used to assess genetic relationships between IGF family members and AF. MR was performed based on genome-wide association study (GWAS) datasets, and concentration levels of 14 IGF family members were retrieved. An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations. A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects. Two-sample MR packages were used to perform MR analysis in R. MR-Egger, weighted median (WM), and inverse variance weighted (IVW) methods were used. In two-sample MR assessments there were lower levels of circulating IGF binding protein 3 in both WM [odds ratio (OR) 0.964, 95% confidence interval (CI) 0.940-0.960, P = 0.006] and IVW (OR 0.968, 95%CI: 0.947-0.987, P = 0.001) analyses. Higher serum levels of IGF2 receptor were associated with AF (OR 1.045, 95%CI: 1.016-1.076, P = 0.039). In reverse MR analysis conducted to investigate casual effects, elevated levels of circulating CYR61 were associated with AF (OR 1.060, 95%CI: 1.005-1.119, P = 0.031). The results of the present study provide novel insights into the pathogenesis of AF, and the implications of serum IGF family member concentrations when assessing the risk of AF. The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF. Further observational and experimental studies are critically needed.

Insulin promotes growth in breast cancer cells through the type I IGF receptor in insulin receptor deficient cells

Breast cancer is the most common cancer in women. The upregulation of insulin-like growth factor (IGF) system observed in certain types of breast cancers was linked to growth, metastasis, and survival resulting in multiple strategies designed to target the type I IGF receptor (IGF-1R) in breast cancer. These attempts failed to prove beneficial and it has been suggested that insulin receptor (IR) could also play an important role in breast cancer biology. To better understand the IR's role in breast cancer cells, the receptor was deleted from MCF-7L cells using CRISPR technology, and fluorescence-assisted cell sorting was used to obtain clone 35 (CL35). It was found that CL35 activated signaling pathways upon insulin stimulation despite the absence of IR expression. We hypothesized that CL35 used a surrogate receptor for sustained growth and development. IGF-1R was able to activate insulin signaling and growth in CL35. Thus, insulin may play a central role in regulating breast cancer growth due to its ability to activate all the receptors of the IGF family. These findings argue that dual targeting of IR and IGF-IR may be required to inhibit breast cancer growth.

Diabetes and ovarian cancer: risk factors, molecular mechanisms and impact on prognosis.

Diabetes mellitus has been linked to a lower rate of cancer survival and an increase in the incidence of most malignancies. Investigations showed that diabetes might affect ovarian cancer (OC) prognosis and survival. Based on the current information, this study intends to review the risk factors, molecular pathways, and impact of diabetes on OC. The data was derived from online databases, including Web of Science, PubMed, and Scopus. The inclusion criteria were original studies, which included the risk factors, molecular mechanisms, and impact of diabetes on OC. The effect of different antidiabetic drugs was also discussed in this manuscript. All of the clinical, in vivo, and in vitro studies were included in the present study. The diagnosis of diabetes mellitus negatively affects the survival and prognosis in OC cases. The epidemiologic data shows that the risk of OC increases in patients with diabetes mellitus compared to the healthy population. Insulin-like growth factors family was raised in diabetic patients, which target several mechanisms, including targeting oxidative stress, angiogenesis, and tumor markers. Antidiabetic drugs such as metformin, sitagliptin, and rosiglitazone have a promising effect on elongation of survival and enhancement of prognosis in OC patients. Diabetes mellitus is a significant risk factor for OC in women, and it negatively impacts survival and prognosis. Molecular mechanisms such as IGF family, oxidative stress, and inflammatory cytokines have been identified to explain this relationship. Antidiabetic drugs like metformin, sitagliptin, and rosiglitazone have shown promise in improving survival and prognosis of OC patients.

Varying severity COVID-19 effects on the blood indicators of insulin-like growth factors family in patients with nonsmall cell lung cancer

Purpose of the study. An analysis of IGF and their carrying proteins levels in blood serum of patients with non‑small cell lung cancer (NSCLC), depending on the severity of the previous COVID-19 infection.Materials and methods. 60 patients with histologically verified NSCLC T2–3NхM0 receiving treatment at the Thoracic Department (National Medical Research Centre for Oncology, 2020–2021), were included in the study. The control group included 30 NSCLC patients after asymptomatic or mild COVID-19 disease (15 men and 15 women); the main group included 30 (15 men and 15 women) patients after severe or moderate to severe COVID-19. The mean age of patients was 59.11 ± 2.89 years. Blood counts of donors of the same age were used as the norm.Results. The levels of IGF-I, IGF-II, IGFBP2 and IGFBP3 in the blood serum of patients with NSCLC of the main and control groups were higher than those of donors by an average of 2.5, 2.1, 1.7 and 2.7 times, respectively (p < 0.05). The concentration of IGFBP1 was higher in the control group compared to the main group, and decreased in relation to donors: in the control in men and women by 1.4 and 1.9 times, and in the main group by 3.0 and 6.4 times, respectively (p < 0.05). The ratios of IGF and IGFBP1 increased in both groups: IGF-I/IGFBP1 – in the control group from 3.8 to 4.2 times, and in the main group from 7.9 to 14.4 times; IGF-II/IGFBP1 – in the control from 2.4 to 4.5 times, and in the main group from 6.6 to 12.7 times in men and women, respectively (p < 0.05).Conclusions. The level of ligands and almost all of the studied carrier proteins, except for IGFBP1, increases in the blood of patients with NSCLC of both sexes, regardless of the severity of COVID-19. The ratio of IGF-I/IGFBP1 and IGF-II/IGFBP1 in the blood increases in both groups, most significantly in the group with severe and moderate COVID-19, which indicates excessive accumulation of IGF levels and may contribute to a more aggressive course of the malignant process.

Indices of insulin-like growth factors family in the lung tissue of patients with non-small cell lung cancer after COVID-19 of various severity

Purpose of the study. An analysis of levels of IGF and their carrying proteins in lung tissues of cancer patients depending on the severity of the previous COVID-19 infection.Patients and methods. The study included 60 patients with histologically verified non-small cell lung cancer (NSCLC) T1–3NхM0 receiving treatment at the Thoracic Department, National Medical Research Centre for Oncology, in 2020–2021. The control group included 30 NSCLC patients after asymptomatic or mild COVID-19 disease (15 males and 15 females); the main group included 30 (15 men and 15 women) patients after severe or moderate to severe COVID-19 infection. The mean age of patients was 59.11 ± 2.89 years; no significant differences were noted between the control and main groups. All participants gave their informed consent prior to the study approved by the Ethics Committee of National Medical Research Centre for Oncology. Qualitative assessment of IGF-I, IGF-II and IGFBP-1,2,3 levels in the tissues of the tumor, peritumoral area and resection line were measured by ELISA (Mediagnost, Germany). The statistical analysis was performed in the Statistica 10 program, the differences were considered statistically significant at p < 0.05.Results. Regardless of the gender, levels of IGF-I and IGF-II in tumor and resection line samples in patients of the main group were higher than in the control group on average by 1.5–2.2 times, and IGFBP-1 in the tumor was lower by 1.3 times in men and by 5 times in women. The ratio of IGF and IGFBP-1-3 in patients of the control group in perifocal tissues changed towards the parameters in the tumor tissue. IGF/IGFBP-1-3 in men of the main group were lower or did not differ from the indices in the intact tissue, while in women they increased, similarly to the tumor tissue.Conclusion. An increase in the ratio of IGF and carrier proteins in the tumor tissue of patients in the main group indicated an excessive accumulation of IGF in it, which may contribute to more aggressive growth of malignant tumors. The most pronounced disorders in the system of insulin-like growth factors were found in the tissues of the tumor and intact lung of patients with previous severe and moderate to severe COVID-19.

Macromolecules Influence Cellular Competence and Expression Level of IGFs Genes in Bovine Oocytes In Vitro.

Simple SummaryThe macromolecule content of culture media can affect the maturation competence of oocytes, which influences the subsequent in vitro development of embryos. This study was designed to determine the effects of macromolecules on cellular competence and the transcript level of insulin-like growth factors (IGF1, IGF2) and their receptors in bovine oocytes. The current study showed that bovine serum albumin (BSA) and fetal calf serum (FCS) improved nuclear maturation and protein biosynthesis (especially FCS). Polyvinyl alcohol did not support the antioxidant defense mechanism due to decreased glutathione peroxidase enzyme activity. The expression of the IGF1 gene could not be detected in all experimental groups, but BSA and FCS increased the transcript level of the IGF2 gene. Moreover, oocyte maturation with BSA increased the transcript level of the IGF1R gene, whereas the transcript level of the IGF2R gene was similar among macromolecule supplementation groups. The BSA and FCS could improve in vitro bovine oocyte development due to supporting cellular characteristics.In vitro maturation (IVM) of mammalian oocytes, which influences subsequent in vitro development of embryos, is affected by the macromolecule content in culture media for the success of oocyte maturation competence, in which the cytoplasmic and nuclear reprogramming events occur. The insulin-like growth factor family (IGFs) promotes the maturation of bovine oocytes and the expansion of cumulus cells and also inhibits apoptosis. This study was, therefore, designed to examine the effects of macromolecules (bovine serum albumin, BSA; fetal calf serum, FCS; and polyvinyl alcohol, PVA) on in vitro nuclear maturation, total cellular protein, glutathione peroxidase (GPx) enzyme activity, and the gene expression level of IGF1, IGF2, and their receptor in bovine oocytes. Oocytes obtained from bovine ovaries were cultured in bicarbonate-buffered medium 199 supplemented with 4 mg/mL BSA, 10% FCS, 1 mg/mL PVA, and without macromolecule supplement (control) during 22 h in the air with a humidified atmosphere and 5% CO2 at 38.5 °C temperature. Supplementation of BSA and FCS increased (χ2 = 9.84; p < 0.05) the percentages of oocytes that reached metaphase II compared to the control and PVA. The amount of protein per ml of cell extracts of oocytes matured in FCS supplemented culture media was higher (p < 0.05) than the oocytes in the PVA and control. The levels of GPx enzyme activity in cell extracts isolated from oocytes in each experimental group did not change over time, but the GPx enzyme activity in oocytes matured in PVA-supplemented culture media was lower (p < 0.05) than in oocytes in the other experimental groups. Transcript for the IGF1 gene was not detected in all experimental groups, but the supplementation of BSA and FCS significantly elevated the transcript level of the IGF2 gene. In addition, the maturation of oocytes with BSA-supplemented media increased the transcript level of the IGF1R gene, whereas the transcript level of the IGF2R gene was similar among macromolecule supplementation groups. The current study concluded that BSA and FCS could improve in vitro bovine oocyte development due to supporting nuclear maturation and increasing the total cellular protein content, GPx enzyme, and transcript activity.

PSI-9 Disrupting Cxcl12-Cxcr4 Chemokine Axis at the Fetal-Maternal Interface During Implantation Results in Altered Expression of Angiogenic and Insulin-Like Growth Factors in Ovine Placenta Midgestation

Abstract Placental dysfunction is a fundamental cause of intrauterine growth restriction, and fetal morbidity and mortality in livestock. Though causes of placental dysfunction are not well characterized, origin of disease transpires during placental development (placentation). The C-X-C motif chemokine ligand 12 (CXCL12) working through its receptor CXCR4 is implicated in placentation but precise roles of this axis are unclear. Using an in vivo sheep model, we demonstrated that suppressing CXCL12-CXCR4 signaling at the fetal-maternal interface reduces placental vascularization. We hypothesized these negative impacts early in gestation would result in compromised placental development and vascularization at midgestation. To test, onday 12 post-breeding, osmotic pumps were surgically installed in 22 ewes and delivered either CXCR4 inhibitor (AMD3100) at 1.5X dose, (n=8) or 3X dose (n=8) or saline (n=6) into the uterine lumen ipsilateral to the corpus luteum for 14 days. On day 90 placental tissues were collected and maternal and fetal placenta components separated and analyzed. The objectives were to determine if suppressing CXCL12-CXCR4 actions at the fetal-maternal interface during implantation results in reduced placental and vascular development at midgestation. Gene expression for angiogenic factors and members of the insulin-like growth factor family were analyzed using Real-time qPCR. Of the targets tested, mRNA expression was significantly altered by AMD3100 treatment for the vascular endothelial growth factor receptors (FLT-1 and KDR) primarily in maternal placenta. Expression of insulin-like growth factors 1 and 2, IGF-binding protein 3, and placental lactogen were significantly altered in fetal placenta with AMD3100 treatment compared to control. Our preliminary data underscore the importance of CXCL12-CXCR4 signaling during placentation and provide strong evidence that altering CXCL12-mediated signaling during early placentation induces enduring placental effects manifesting later in gestation. A greater understanding of CXCL12/CXCR4 functions may reveal methods to improve reproductive success and fetal health.

IGFs in Dentin Formation and Regeneration: Progress and Remaining Challenges.

Tertiary dentin results from the interplay between the host defense and dental injury or infection. Modern endodontics aiming vital pulp treatment take the tertiary dentin formation as the interim step, with the final goal of a physiological pulp-dentin like tissue regeneration. Dental pulp stem cells have been nominated for contributing to differentiating into odontoblast-like cells who are responsible for reparative dentin formation. Understanding the original dentin formation mechanism provides us a blueprint while exploring the reparative dentin formation mechanism builds bridge to bonafide pulp-dentin tissue regeneration. Among all the regulators, growth factors have long been revealed under the spotlight. The insulin-like growth factor (IGF) family has been implicated in critical events of inducing dentin formation, which is essential for pulp treatment. The expression of IGF family members including IGF1, IGF1R, IGF2, and IGF2R has been well characterized in dental papilla cells, dental pulp stem cells, and periodontal ligament cells. Recent studies indicated IGF binding to the receptors activated pathways, including MAPK pathway, and AKT pathway, orchestrated proliferation, and differentiation, and finally, contributed to dentin formation. This review summarizes the role of IGF family in dentin formation during tooth development and tertiary dentin formation during dentin-pulp repair and sheds light on key parts of research for future treatment improvements.

IGFBP-3 Regulates Mitochondrial Hyperfusion and Metabolic Activity in Ocular Surface Epithelia during Hyperosmolar Stress.

In the eye, hyperosmolarity of the precorneal tear film triggers inflammation and the development of dry eye disease (DED), a highly prevalent condition that causes depression and disability in severe forms. A member of the insulin-like growth factor (IGF) family, the IGF binding protein-3 (IGFBP-3), is a pleiotropic protein with known roles in growth downregulation and survival. IGFBP-3 exerts these effects by blocking IGF-1 activation of the type 1 IGF-receptor (IGF-1R). Here, we examined a new IGF-independent role for IGFBP-3 in the regulation of mitochondrial and metabolic activity in ocular surface epithelial cells subject to hyperosmolar stress and in a mouse model of DED. We found that hyperosmolar stress decreased IGFBP-3 expression in vitro and in vivo. Treatment with exogenous IGFBP-3 induced an early, transient shift in IGF-1R to mitochondria, followed by IGFBP-3 nuclear accumulation. IGFBP-3 nuclear accumulation increased protein translation, blocked the hyperosmolar-mediated decrease in oxidative phosphorylation through the induction of mitochondrial hyperfusion, and restored corneal health in vivo. These data indicate that IGFBP-3 acts a stress response protein in ocular surface epithelia subject to hyperosmolar stress. These findings may lead to the development of first-in-class therapeutics to treat eye diseases with underlying mitochondrial dysfunction.

Metformin, clomiphene citrate and flutamide effects on oocyte ultrastructure status and quality in PCOS mouse model

Research questionPolycystic ovary syndrome (PCOS) alters oocyte developmental competence and so the treatment of PCOS patients with assisted reproductive techniques is a major challenge for an infertility specialist. Does ovulation induction therapy with clomiphene citrate, metformin and flutamide affect abnormal PCOS follicle gene expression, its quality, and nuclear and cytoplasmic maturation in the oocyte matured in vitro? DesignFifty NMRI mice (7–8 weeks old) were randomly divided into five groups, including non-PCOS, PCOS and PCOS groups treated with clomiphene citrate (18 mg/kg body weight for 2 days), metformin (50 mg/100 g body weight for 30 days) and flutamide (10 mg/kg body weight injection for 15 days). The oocytes were collected for quantitative real-time polymerase chain reaction analysis (the evaluation of genes associated with oocyte maturation), transmission electron microscopy (the evaluation of cytoplasmic maturation) and in-vitro maturation (IVM) and IVF outcomes. ResultsThe dysregulated expression of some genes of insulin-like growth factor (IGF) families involved in oocyte competence and steroid metabolism (e.g. Cyp19a1 and Cyp11a1), transforming growth factor beta (TGF-β) family (e.g. Tgfb1, Gdf9, Bmp15, Inhbb and Bmpr1a), and oestrogen receptor signalling (e.g. Ncoa3, Pgr) was, to some extent, restored in the PCOS follicles following their with clomiphene citrate, metformin and flutamide. The improved cytoplasmic maturation was observed particularly in the PCOS mice treated with clomiphene citrate. The better IVM–IVF outcomes were also observed in the clomiphene citrate and metformin groups compared with the PCOS group. ConclusionsThis study opens up a new perspective on knowing the effect of ovulation induction therapy on not only nuclear maturation but also ultrastructural characteristics, IVM–IVF outcomes and PCOS oocyte developmental competence.

The role of IGF-pathway biomarkers in determining risks, screening, and prognosis in lung cancer.

Background: Detection rates of early-stage lung cancer are traditionally low, which contributes to inconsistent treatment responses and high rates of annual cancer deaths. Currently, low-dose computed tomography (LDCT) screening produces a high false discovery rate. This limitation has prompted research to identify biomarkers to more clearly define eligible patients for LDCT screening, differentiate indeterminate pulmonary nodules, and select individualized cancer therapy. Biomarkers within the Insulin-like Growth Factor (IGF) family have come to the forefront of this research.Main Body: Multiple biomarkers within the IGF family have been investigated, most notably IGF-I and IGF binding protein 3. However, newer studies seek to expand this search to other molecules within the IGF axis. Certain studies have demonstrated these biomarkers are useful when used in combination with lung cancer screening, but other findings were not as conclusive, possibly owing to measurement bias and non-standardized assay techniques. Research also has suggested IGF biomarkers may be beneficial in the prognostication and subsequent treatment via systemic therapy. Despite these advances, additional knowledge of complex regulatory mechanisms inherent to this system are necessary to more fully harness the potential clinical utility for diagnostic and therapeutic purposes.Conclusions: The IGF system likely plays a role in multiple phases of lung cancer; however, there is a surplus of conflicting data, especially prior to development of the disease and during early stages of detection. IGF biomarkers may be valuable in the screening, prognosis, and treatment of lung cancer, though their exact application requires further study.

Abstract P4-02-01: Targeting insulin receptor in estrogen receptor positive breast cancer

Abstract Obesity and metabolic dysfunction are on the rise in the United States. Hyperinsulinemia, frequently seen in these conditions, correlates with an increased risk of development and mortality from estrogen receptor (ER) positive breast cancer. Expression of components of the insulin and insulin-like growth factor (IGF) family of proteins promote cancer cell growth in vitro, link to shorter progression-free survival, and is associates with an increased risk of metastatic disease and death in breast cancer patients. Previously our lab found that development of resistance to the commonly used ER-targeting drug tamoxifen (Tam) in vitro is associated with a loss of the type I IGF receptor expression with an increased dependence on the homologous insulin receptor (IR). These data argue for targeting IR in breast cancer, but concern has been raised due to the potential of disrupting glucose homeostasis in patients with or without existing metabolic disease. To address this concern, a novel insulin-Fc fusion protein (AKS-130) was developed to lower blood glucose levels without causing clinical hypoglycemia with a potential to target tumor IR. AKS-130 was found to downregulate IR expression in models of colorectal cancer (HCT-116) and malignant melanoma (WM266.4). Further, AKS-130 suppressed xenograft growth in fed and fasted states. We examined if AKS-130 had similar effects on ER positive breast cancer cells. To test the hypothesis that resistance to endocrine therapy increases the reliance of ER positive breast cancer cells on IR signaling, we utilized the ER positive breast cancer cell lines (MCF-7L, T47D) and their Tam resistant derivatives (MCF-7L TamR, T47D TamR). Similar to in HCT-116 and WM266.4 cells, we found that AKS-130 is a modest agonist of IR in ER+ breast cancer cells. Exposure to AKS-130 led to a marked reduction in IR expression in both parental and TamR cell lines, and was associated with partially suppressed downstream signaling to Akt. Interestingly, AKS130 induced IR downregulation was inhibited by pretreatment of BMS 536924, a dual IGF1R/IR kinase inhibitor. In vivo, AKS-130 treatment by itself scaled down MCF7L parental xenograft growth as compared to vehicle group, and AKS-130 in combination with Tam trended toward extending time to a tumor size of 500mm3. In MCF7L TamR xenografts, addition of AKS-130 to Tam treatment also trended toward delaying xenograft growth, though it was not statistically significant. Importantly, prolonged treatment with AKS-130 did not lead to significant changes in weight or blood glucose. Taken together these data show that novel agents, such as AKS-130, may serve as way to disrupt IR signaling in cancer cells without affecting host glucose metabolism. Addition of AKS-130 to Tam treatment trended toward delaying xenograft growth though further studies are needed, especially animal model systems of insulin resistance. These data indicate that IR signaling may represent a target to overcome or delay endocrine therapy resistance in breast cancer. Citation Format: Jingran Cao, Lynsey M. Fettig, Kelly LaPara, Xihong Zhang, Sylaja Murikipudi, Andrea R. Delpero, Thomas M. Lancaster, Todd C. Zion, Douglas Yee. Targeting insulin receptor in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-01.

IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.

Mitochondrial dysfunction or loss of homeostasis is a central hallmark of many human diseases. Mitochondrial homeostasis is mediated by multiple quality control mechanisms including mitophagy, a form of selective autophagy that recycles terminally ill or dysfunctional mitochondria in order to preserve mitochondrial integrity. Our prior studies have shown that members of the insulin-like growth factor (IGF) family localize to the mitochondria and may play important roles in mediating mitochondrial health in the corneal epithelium, an integral tissue that is required for the maintenance of optical transparency and vision. Importantly, the IGF-binding protein-3, IGFBP-3, is secreted by corneal epithelial cells in response to stress and functions to mediate intracellular receptor trafficking in this cell type. In this study, we demonstrate a novel role for IGFBP-3 in mitochondrial homeostasis through regulation of the short isoform (s)BNIP3L/NIX mitophagy receptor in corneal epithelial cells and extend this finding to non-ocular epithelial cells. We further show that IGFBP-3-mediated control of mitochondrial homeostasis is associated with alterations in lamellar cristae morphology and mitochondrial dynamics. Interestingly, both loss and gain of function of IGFBP-3 drive an increase in mitochondrial respiration. This increase in respiration is associated with nuclear accumulation of IGFBP-3. Taken together, these findings support a novel role for IGFBP-3 as a key mediator of mitochondrial health in mucosal epithelia through the regulation of mitophagy and mitochondrial morphology.

Insulin-like growth factor 2 (IGF2) gene: molecular characterization, expression analysis and association of polymorphisms with egg production traits in goose (Anser cygnoides)

Insulin-like growth factor 2 (IGF2) belongs to the member of the insulin-like growth factors family, which plays key roles in animal growth, differentiation and proliferation, as well as reproduction and the regulation of ovarian follicle development. However, little is known about the goose IGF2 gene. In this study, a 1879 bp fragment that covered the complete coding region (CDS) of goose IGF2 cDNA was identified for the first time. The cDNA consists of an open reading frame of 574 nucleotides with the capacity to encode a prepro-IGF-II protein of 187 amino acids, which comprises a signal peptide (24 residues), IGF-II peptide (67 residues), and C-terminal peptide (96 residues), and is closely related to that of chicken. qPCR indicates that the goose IGF2 mRNA is differentially expressed in all examined tissues of fertilized eggs (28 days) and laying Zhedong White geese (270 days). Two novel single nucleotide polymorphisms (SNPs) were detected in exon 1 (G63A, Chr2: G26541617A) and intron 1 (G38A, Chr2: G26541479A) regions, and the synonymous mutation G63A showed a significant association with egg numbers (E180d) of Sanhua goose population (p < 0.05). All the information derived from this study could be valuable and facilitate further studies on the functions of goose IGF2 gene.

Colostrogenesis: Role and Mechanism of the Bovine Fc Receptor of the Neonate (FcRn).

Colostrogenesis is a separate and unique phase of mammary epithelial cell activity occurring in the weeks before parturition and rather abruptly ending after birth in the bovine. It has been the focus of research to define what controls this process and how it produces high concentrations of specific biologically active components important for the neonate. In this review we consider colostrum composition and focus upon components that appear in first milked colostrum in concentrations exceeding that in blood serum. The Fc Receptor of the Neonate (FcRn) is recognized as the major immunoglobulin G (IgG) and albumin binding protein that accounts for the proteins' long half-lives. We integrate the action of the pinocytotic (fluid phase) uptake of extracellular components and merge them with FcRn in sorting endosomes. We define and explore the means of binding, sorting, and the transcytotic delivery of IgG1 while recycling IgG2 and albumin. We consider the means of releasing the ligands from the receptor within the endosome and describe a new secretion mechanism of cargo release into colostrum without the appearance of FcRn itself in colostrum. We integrate the insulin-like growth factor family, some of which are highly concentrated bioactive components of colostrum, with the mechanisms related to FcRn endosome action. In addition to secretion, we highlight the recent findings of a role of the FcRn in phagocytosis and antigen presentation and relate its significant and abrupt change in cellular locationafter parturition to a role in the prevention and resistance to mastitis infections.

Molecular identification of Igf3 and its roles in grass carp (Ctenopharyngodon idella)

As a new member of the Insulin-like growth factors (IGFs) family of proteins, Igf3 has been found to be involved in fish reproduction. To evaluate the functions of Igf3 in grass carp, the igf3 gene was isolated from the gonads via RT-PCR (reverse transcription polymerase chain reaction). The ORF of grass carp igf3 was found to be 606 bp long, encoding 201 amino acids. The grass carp Igf3 precursor contains five domains, termed B-C-A-D-E. Tissues distribution analysis showed that igf3 was widely expressed in multiple tissues, and is highly expressed in the gonads, cerebellum and hypothalamus of grass carp. The oral glucose tolerance test (OGTT) showed that igf3 expression levels increased in the hypothalamus, hepatopancreas and muscle after glucose treatment. The fasting/refeeding showed that igf3 expression in hepatopancreas and muscle were markedly inhibited in the fasting group and were significantly increased in refeeding group. A recombinant grass carp Igf3 protein was obtained using a prokaryotic expression system. The function of this recombinant Igf3 were assessed in vitro and in vivo experiments. The expression of igf1, igf2b, and ghr was significantly increased, and igf2a expression was markedly decreased by Igf3 treatment in vitro and in vivo. The expression of igf3 and igf1r was significantly increased by Igf3 treatment in vitro. The expression of igfbp1 decreased and the expression of igfbp2, igfbp3, akt and pi3k increased after Igf3 treatment in vivo and in vitro. The expression of igfbp5a and igfbp5b were also increased by Igf3 treatment in vitro. The effects of Igf3 treatment on the expression of igf1, igf2, and ghr were relieved after treatment with the PI3K inhibitor wortmannin in grass carp primary hepatocytes. To our knowledge, our study was the first to reveal that Igf3 regulates the expression of growth-related genes in teleosts.

The IGF-1 Signaling Pathway in Viral Infections.

Insulin-like growth factor-1 (IGF-1) and the IGF-1 receptor (IGF-1R) belong to the insulin-like growth factor family, and IGF-1 activates intracellular signaling pathways by binding specifically to IGF-1R. The interaction between IGF-1 and IGF-1R transmits a signal through a number of intracellular substrates, including the insulin receptor substrate (IRS) and the Src homology collagen (Shc) proteins, which activate two major intracellular signaling pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways, specifically the extracellular signal-regulated kinase (ERK) pathways. The PI3K/AKT kinase pathway regulates a variety of cellular processes, including cell proliferation and apoptosis. IGF1/IGF-1R signaling also promotes cell differentiation and proliferation via the Ras/MAPK pathway. Moreover, upon IGF-1R activation of the IRS and Shc adaptor proteins, Shc stimulates Raf through the GTPase Ras to activate the MAPKs ERK1 and ERK2, phosphorylate and several other proteins, and to stimulate cell proliferation. The IGF-1 signaling pathway is required for certain viral effects in oncogenic progression and may be induced as an effect of viral infection. The mechanisms of IGF signaling in animal viral infections need to be clarified, mainly because they are involved in multifactorial signaling pathways. The aim of this review is to summarize the current data obtained from virological studies and to increase our understanding of the complex role of the IGF-1 signaling axis in animal virus infections.