Insulin Receptor Substrate-1 (IRS-1) and IRS-2 expression levels are associated with prognosis in non-small cell lung cancer (NSCLC)

Piper, Andrew; Clark, Jennifer L.; Mercado-Matos, Jose; Matthew-Onabanjo, Asia N.; Hsieh, Chung‐Cheng; Akalin, Ali; Shaw, Leslie M.

doi:10.1371/journal.pone.0220567

Cited by 22 publications

(20 citation statements)

References 34 publications

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“…Chronic hyperinsulinemia has been proposed to play a role in the growth of non-small-cell lung cancer, with data suggesting that chronic stimulation of the insulin-like growth factor-1 signaling pathway may promote the rapid growth of existing neoplasms [19,20]. This observation is supported by data demonstrating an overall increased risk of any malignancy in the population of patients with long-standing diabetes.…”

Section: Discussionmentioning

confidence: 90%

Comprehensive Pulmonary Safety Review of Inhaled Technosphere® Insulin in Patients with Diabetes Mellitus

et al. 2020

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Background and Objective Technosphere ® Insulin (TI), a human insulin powder for inhalation (Afrezza ® ; MannKind Corporation, Westlake Village, CA, USA), is an ultra-rapid-acting inhaled insulin indicated to improve postprandial glycemic control in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). Because TI is absorbed across the alveolar membrane, the objective of this analysis was to characterize its pulmonary safety. Methods Pooled data from 13 phase 2/3 clinical studies in 5505 patients with T1DM or T2DM treated with TI, Technosphere inhalation powder without insulin (TP; placebo), or active-comparator treatment were analyzed for incidences of respiratory treatment-emergent adverse events (TEAEs), changes in pulmonary function, and lung malignancies. Radiographic changes in the lungs were monitored in a subset of 229 patients. Results Among 3017 patients receiving TI, the median duration of TI exposure was 168 days; median active-comparator and TP exposure durations were 363 and 149 days for 2198 and 290 patients, respectively. Respiratory TEAEs were comparable across treatments, except for a higher incidence of mild cough with TI in active-comparator studies (28.0% vs. 5.2%). Slight reversible declines in pulmonary function from baseline were observed for TI versus TP and active-comparator treatments, including in a subpopulation of patients with retrospectively identified lung dysfunction. Lung malignancies were reported in two patients on active TI therapy with a smoking history. No clinically significant changes from baseline were observed in radiographic images. Conclusions Pulmonary safety assessment of the TI inhalation system did not identify any safety issues in individuals with either T1DM or T2DM.

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Section: Discussionmentioning

confidence: 90%

Comprehensive Pulmonary Safety Review of Inhaled Technosphere® Insulin in Patients with Diabetes Mellitus

et al. 2020

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“…IRS2, a cytoplasmic adaptor protein, mediates the effects of insulin as well as IGF1 and therefore plays a role in growth-promoting IGF1 receptor (IGF1R) signaling. Overexpression is associated with increased glucose metabolism and tumor invasion as well as decreased overall survival and disease progression in patients [ 97 , 98 ]. Therefore, the downregulation of IRS2 by hyperinsulinemia lowered tumor invasion and metastasis in the present study, which has also been proven in an obese and diabetic mouse model [ 99 , 100 ].…”

Section: Discussionmentioning

confidence: 99%

Changes in protein expression due to metformin treatment and hyperinsulinemia in a human endometrial cancer cell line

Lange

Weber

Schmidt³

et al. 2021

PLoS ONE

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The incidence of endometrial cancer (EC) has increased over the past years and mainly affects women above the age of 45 years. Metabolic diseases such as obesity and type II diabetes mellitus as well as associated conditions like polycystic ovary syndrome (PCOS), insulin resistance and hyperinsulinemia lead to elevated levels of circulating estrogens. Increased estrogen concentrations, in turn, further trigger the proliferation of endometrial cells and thus promote EC development and progression, especially in the absence of progesterone as seen in postmenopausal women. Elevated blood glucose levels in diabetic patients further contribute to the risk of EC development. Metformin is an insulin-sensitizing biguanide drug, commonly used in the treatment of type II diabetes mellitus, especially in obese patients. Besides its effects on glucose metabolism, metformin displayed anti-cancer effects in various cancer types, including EC. Direct anti-cancer effects of metformin target signaling pathways that are involved in cellular growth and proliferation, e.g. the AKT/PKB/mTOR pathway. Further proteins and pathways have been suggested as potential targets, but the underlying mechanism of action of metformin’s anti-cancer activity is still not completely understood. In the present study, the effects of metformin on protein expression were investigated in the human EC cell line HEC-1A using an affinity proteomic approach. Cells were treated with 0.5 mmol/L metformin over a period of 7 days and changes in the expression pattern of 1,300 different proteins were compared to the expression in untreated control cells as well as insulin-treated cells. Insulin treatment (100 ng/mL) was incorporated into the study in order to implement a model for insulin resistance and associated hyperinsulinemia, conditions that are often observed in obese and diabetic patients. Furthermore, the culture medium was supplemented with 10 nmol/L ß-estradiol (E2) during treatments to mimic increased estrogen levels, a common risk factor for EC development. Based on the most prominent and significant changes in expression, a set of 80 proteins was selected and subjected to a more detailed analysis. The data revealed that metformin and insulin targeted similar pathways in the present study and mostly acted on proteins related to proliferation, migration and tumor immune response. These pathways may be affected in a tumor-promoting as well as a tumor-suppressing way by either metformin treatment or insulin supplementation. The consequences for the cells resulting from the detected expression changes were discussed in detail for several proteins. The presented data helps identify potential targets affected by metformin treatment in EC and allows for a better understanding of the mechanism of action of the biguanide drug’s anti-cancer activity. However, further investigations are necessary to confirm the observations and conclusions drawn from the presented data after metformin administration, especially for proteins that were regulated in a favorable way, i.e. AKT3, CCND2, CD63, CD81, GFAP, IL5, IL17A, IRF4, PI3, and VTCN1. Further proteins might be of interest, where metformin counteracted unfavorable effects that have been induced by hyperinsulinemia.

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“…Interestingly, Han et al reported that 43.6% of NSCLC specimens showed loss of IRS-1 expression, and downregulation of IRS-1 is more frequently observed in squamous cell carcinoma than other type lung cancer [ 40 ]. Meanwhile, low IRS-1 cytoplasmic expression also showed a trend toward association with decreased overall survival in squamous cell carcinoma patients [ 41 ]. In this study, IRS-1 was relatively highly expressed in A549, H1299, and LTEP-a2 cells, which might be due to these NSCLC cells being adenocarcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

Insulin Receptor Substrate 1 Is Involved in the Phycocyanin-Mediated Antineoplastic Function of Non-Small Cell Lung Cancer Cells

Hao

Liu

et al. 2021

Molecules

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Phycocyanin, derived from marine algae, is known to have noteworthy antineoplastic properties. However, the underlying mechanism involved in phycocyanin-mediated anti-growth function on non-small cell lung cancer (NSCLC) cells is still ambiguous. Here, we investigated the mechanism of action of phycocyanin on H1299, A549, and LTEP-a2 cells. According to the results obtained, insulin receptor substrate 1 (IRS-1) expression was reduced by phycocyanin. Cell phenotype tests showed that siRNA knockdown of IRS-1 expression significantly inhibited the growth, migration, colony formation, but promoted the apoptosis of NSCLC cells. Meanwhile, phycocyanin and IRS-1 siRNA treatment both reduced the PI3K-AKT activities in NSCLC cells. Moreover, overexpression of IRS-1 accelerated the proliferation, colony formation, and migration rate of H1299, A549, and LTEP-a2 cells, which was contradicting to the knockdown results. Overall, this study uncovered a regulatory mechanism by which phycocyanin inhibited the growth of NSCLC cells via IRS-1/AKT pathway, laying the foundation for the potential target treatment of NSCLC.

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Insulin Receptor Substrate-1 (IRS-1) and IRS-2 expression levels are associated with prognosis in non-small cell lung cancer (NSCLC)

Cited by 22 publications

References 34 publications

Comprehensive Pulmonary Safety Review of Inhaled Technosphere® Insulin in Patients with Diabetes Mellitus

Comprehensive Pulmonary Safety Review of Inhaled Technosphere® Insulin in Patients with Diabetes Mellitus

Changes in protein expression due to metformin treatment and hyperinsulinemia in a human endometrial cancer cell line

Insulin Receptor Substrate 1 Is Involved in the Phycocyanin-Mediated Antineoplastic Function of Non-Small Cell Lung Cancer Cells

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