The Insulin Receptor: An Important Target for the Development of Novel Medicines and Pesticides

Zhang, Xiaohong; Zhu, Xinyao; Bi, Xiaoyang; Huang, Jiguang; Zhou, Lijuan

doi:10.3390/ijms23147793

Cited by 25 publications

(13 citation statements)

References 282 publications

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“…We thus propose that the combination of chemotherapy with INSR inhibitors and NAMPT inhibitors could represent a promising treatment strategy for early chemoresistant HGSOC patients. The inhibitors of NAMPT and INSR have undergone extensive development and clinical testing (58,59). Previous research has demonstrated that the combination of a NAMPT inhibitor and chemotherapy resulted in a better prognosis than chemotherapy alone in mice with HGSOC (60), holds promise for further improving the therapeutic window.…”

Section: Discussionmentioning

confidence: 99%

Pre-existing cancer cells and induced fibroblasts are key cells for early chemoresistance in ovarian cancer

Gu,

He,

et al. 2024

Preprint

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Chemoresistance has long been a significant but unresolved issue in the treatment of various cancers, including the most deadly gynecological cancer, the high-grade serous ovary cancer (HGSOC). In this study, single nuclei transcriptome analyses were utilized to identify key cells and core networks for chemoresistance in HGSOC patients with different early responses to platinum-based chemotherapy at the single-cell level. Biomarkers for chemoresistance were also screened using bulk transcriptome data from independent cohorts with larger sample sizes. A total of 62,482 single cells from six samples were analyzed, revealing that chemoresistant cancer cells (Epithelial cells_0) pre-existed within individual patient before treatment. Two network modules formed with hub genes such as hormone-related genes (ESR1 and AR), insulin-related genes (INSR and IGF1R), and CTNNB1, were significantly overexpressed in these cells in the chemoresistant patient. BMP1 and TPM2 could be promise biomarkers in identifying chemoresistant patients before chemotherapy using bulk transcriptome data. Additionally, chemotherapy-induced fibroblasts (Fibroblasts_01_after) emerged as key stromal cells for chemoresistance. One network module containing one subnetwork formed by cholesterol biosynthesis-related genes and one subnetwork formed by cancer-related genes such as STAT3 and MYC, was significantly overexpressed in these cells in the chemoresistant patient. Notably, the NAMPT-INSR was the most prioritized ligand-receptor pair for cells interacting with Fibroblasts_01_after cells and Epithelial cells_0 cells to drive the up-regulation of their core genes, including IL1R1, MYC and INSR itself. Our findings deepen the understandings about mechanisms of early chemoresistance in HGSOC patients.

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Section: Discussionmentioning

confidence: 99%

Pre-existing cancer cells and induced fibroblasts are key cells for early chemoresistance in ovarian cancer

Gu,

He,

et al. 2024

Preprint

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“…There are several upstream signalling events in GLUT4 translocation stimulated by insulin binding to its receptor on the membrane of target cells [ 36 ]. The extracellular α subunit of the insulin receptor undergoes a conformational change upon binding with insulin, leading to the facilitation of ATP binding to the β subunit of the receptor [ 52 ]. This triggers the phosphorylation of intracellular substrate proteins and insulin-responsive substrates (IRSs) and further mediates insulin-mediated downstream signalling events, leading to GLUT4 movement and glucose uptake (as depicted in Figure 1 ) [ 53 ].…”

Section: Glucose Metabolismmentioning

confidence: 99%

Capsaicin and Zinc Signalling Pathways as Promising Targets for Managing Insulin Resistance and Type 2 Diabetes

et al. 2023

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The global burden of type 2 diabetes (T2DM) has led to significant interest in finding novel and effective therapeutic targets for this chronic disorder. Bioactive food components have effectively improved abnormal glucose metabolism associated with this disease. Capsaicin and zinc are food components that have shown the potential to improve glucose metabolism by activating signalling events in the target cells. Capsaicin and zinc stimulate glucose uptake through the activation of distinct pathways (AMPK and AKT, respectively); however, calcium signal transduction seems to be the common pathway between the two. The investigation of molecular pathways that are activated by capsaicin and zinc has the potential to lead to the discovery of new therapeutic targets for T2DM. Therefore, this literature review aims to provide a summary of the main signalling pathways triggered by capsaicin and zinc in glucose metabolism.

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“…Briefly, the insulin/insulin receptor signaling cascade consists of two main branches emanating from the insulin receptor-insulin receptor substrate (IRS) node: the phosphatidylinositol 3-kinase (PI3K, a lipid kinase)/AKT (also known as PKB or protein kinase B) pathway and the Raf/Ras/MEK/MAPK (mitogen activated protein kinase, also known as ERK or extracellular signal regulated kinase) pathway [ 136 , 137 , 138 ]. After phosphorylation on tyrosine residues in their C-termini, IRS adaptor proteins serve as docking sites for the recruitment of downstream signaling effectors [ 139 , 140 ]. What may be relevant in PCOS is that the coexistence of inflammatory signaling via the NF-κB and activator protein 1 (AP-1)/c-Fos/c-Jun pathways results in the activation of serine kinases, I-kappa-B-kinase beta (IKKβ) and c-Jun N-terminal kinase 1 (JNK1), with a subsequent reduction in IRS signaling ability.…”

Section: Epigenetic Regulation Of Insulin Resistance and Inflammatory...mentioning

confidence: 99%

Modulation of the Inflammatory Response in Polycystic Ovary Syndrome (PCOS)—Searching for Epigenetic Factors

Szukiewicz

Trojanowski

Kociszewska

et al. 2022

IJMS

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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Despite its incidence, the syndrome is poorly understood and remains underdiagnosed, and female patients are diagnosed with a delay. The heterogenous nature of this complex disorder results from the combined occurrence of genetic, environmental, endocrine, and behavioral factors. Primary clinical manifestations of PCOS are derived from the excess of androgens (anovulation, polycystic ovary morphology, lack of or scanty, irregular menstrual periods, acne and hirsutism), whereas the secondary manifestations include multiple metabolic, cardiovascular, and psychological disorders. Dietary and lifestyle factors play important roles in the development and course of PCOS, which suggests strong epigenetic and environmental influences. Many studies have shown a strong association between PCOS and chronic, low-grade inflammation both in the ovarian tissue and throughout the body. In the vast majority of PCOS patients, elevated values of inflammatory markers or their gene markers have been reported. Development of the vicious cycle of the chronic inflammatory state in PCOS is additionally stimulated by hyperinsulinemia and obesity. Changes in DNA methylation, histone acetylation and noncoding RNA levels are presented in this review in the context of oxidative stress, reactive oxygen species, and inflammatory signaling in PCOS. Epigenetic modulation of androgenic activity in response to inflammatory signaling is also discussed.

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The Insulin Receptor: An Important Target for the Development of Novel Medicines and Pesticides

Cited by 25 publications

References 282 publications

Pre-existing cancer cells and induced fibroblasts are key cells for early chemoresistance in ovarian cancer

Pre-existing cancer cells and induced fibroblasts are key cells for early chemoresistance in ovarian cancer

Capsaicin and Zinc Signalling Pathways as Promising Targets for Managing Insulin Resistance and Type 2 Diabetes

Modulation of the Inflammatory Response in Polycystic Ovary Syndrome (PCOS)—Searching for Epigenetic Factors

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