Insulin analogues display IGF‐I‐like mitogenic and anti‐apoptotic activities in cultured cancer cells

Weinstein, Doron; Simon, Meital; Yehezkel, Einat; Laron, Zvi; Werner, Haim

doi:10.1002/dmrr.912

Cited by 162 publications

(156 citation statements)

References 28 publications

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“…Biological studies have shown that insulin glargine and insulin detemir have a positive effect on cell cycle progression and display anti-apoptotic activities [14,25]. These results are consistent with our signalling analyses, showing that insulin glargine exhibited IGF-I-like activity in terms of IGF-IR phosphorylation, internalisation and cellular re-distribution.…”

Section: Discussionsupporting

confidence: 91%

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Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor

et al. 2010

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Aims/hypothesis Insulin analogues were developed to improve the pharmacological properties of injected insulin and to better mimic endogenous insulin output. However, certain insulin analogues have been suggested to display IGF-I-like biological activities. Furthermore, several recent epidemiological studies have suggested a potential increase in cancer risk for treatment of diabetes patients with longacting analogue insulin glargine (A21Gly,B31Arg,B32Arg human insulin). Additional studies, however, reported no increased cancer risk. The purpose of the present study was to identify the receptor(s) and signal transduction pathways responsible for the biological actions of insulin glargine and insulin detemir (B29Lys[ε-tetradecanoyl],desB30 human insulin). Methods The colon cancer-derived cell line HCT116 was treated with increasing doses of insulin glargine, insulin detemir, regular insulin or IGF-I, and receptor activation was evaluated by immunoprecipitation assays. IGF-I receptor (IGF-IR) internalisation following insulin glargine treatment was assessed by confocal microscopy. Activation of the Akt and extracellular signal-regulated kinase pathways was evaluated by western blots. The anti-apoptotic effect of the analogues was measured by poly-(ADP ribose) polymerase antibody and annexin assays. Results We found evidence for dual activation of the insulin receptor and IGF-IR by the analogues. Dosedependency experiments showed that insulin glargine was able to phosphorylate the IGF-IR at fivefold lower doses than those required to activate the insulin receptor. We also showed that insulin glargine can lead to prolonged activation of the receptors and therefore promote abnormal signalling. Confocal imaging experiments showed that insulin glargine, but not regular insulin induced IGF-IR internalisation similarly to IGF-I. Finally, both analogues displayed IGF-I-like anti-apoptotic activities and stimulated cell cycle progression. Conclusions/interpretation Our data indicate that insulin glargine and insulin detemir display atypical signalling activities that differ from those elicited by regular insulin and involve activation of the anti-apoptotic IGF-IR.

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Section: Discussionsupporting

confidence: 91%

“…In a recent study, we investigated the biological actions of a series of long-acting and short-acting insulin analogues in cell lines derived from human cancers [14]. The actions evaluated included enhancement of cancer cell proliferation and protection from apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor

et al. 2010

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“…A pancreatic cancer cell line responded similarly to insulin glargine and human insulin, and survival of insulin glargine-treated patients following treatment for pancreatic cancer did not differ from that of patients on insulin or controls [34]. In another study, colorectal, breast and prostate cell lines showed proliferative changes and increased resistance to apoptosis in response to exposure to pharmacological doses of insulin glargine, insulin detemir and insulin lispro, but not to human insulin [35]. Another recent paper tested the effect of exposure to insulin analogues on a panel of neoplastic and non-neoplastic mammary epithelial cell lines.…”

Section: Insulin Analogues and Cancermentioning

confidence: 94%

Does diabetes therapy influence the risk of cancer?

2009

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“…Ferguson et al (2012) have recently shown that high systemic insulin levels promote breast cancer metastasis in a hyperinsulinemic mouse model by activating c-myc signaling. It has been shown that high-dose human insulin and its analogs promoted T24 (bladder cancer cell), , and PC-3 (prostate cancer cell) proliferation (Weinstein et al 2009, Liu et al 2011b. These reports indicate that metabolic changes occurring in patients with hyperglycemia and hyperinsulinemia lead to increased susceptibility of breast cancer progression.…”

Section: Introductionmentioning

confidence: 98%

High glucose and insulin differentially modulates proliferation in MCF-7 and MDA-MB-231 cells

Gupta

Tikoo

2013

Journal of Molecular Endocrinology

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Various preclinical and clinical studies have linked diabetes and breast cancer, but little is known regarding the molecular mechanism involved. This study aimed to investigate the effect of high glucose and insulin in breast cancer cells (MCF-7: non-invasive, hormone dependent, and MDA-MB-231: invasive, hormone independent). In contrast to MCF-7 cells, high glucose augmented proliferation of MDA-MB-231 cells as observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and bromodeoxyuridine assays. The high-glucose condition led to increased expression of cyclin D1, de-phosphorylation of p38, and increased phosphorylation of ERK in MDA-MB-231 cells but not in MCF-7 cells. Interestingly, we observed increased phosphorylation of GSK-3b, NF-kB, and ERa only in MCF-7 cells, highlighting their role as potential targets in prevention of progression of breast cancer under a high-glucose and insulin condition. Furthermore, insulin treatment under a high-glucose condition resulted in increased histone H3 phosphorylation and de-acetylation only in MDA-MB-231 cells. Taken together, we provide the first evidence that high glucose and insulin promotes proliferation of MDA-MB-231 cells by differential alteration of GSK-3b, NF-kB, and ERa expression and histone H3 modifications, which may directly or indirectly modulate the expression of genes involved in its proliferation.

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Insulin analogues display IGF‐I‐like mitogenic and anti‐apoptotic activities in cultured cancer cells

Abstract: Background

Cited by 162 publications

References 28 publications

Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor

Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor

Does diabetes therapy influence the risk of cancer?

High glucose and insulin differentially modulates proliferation in MCF-7 and MDA-MB-231 cells

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