Inhibition of IRS-1 Phosphorylation and the Alterations of GLUT4 in Isolated Adipocytes from Cachectic Tumor-Bearing Rats

Yoshikawa, Takaki; Noguchi, Yoshikazu; Satoh, Shinobu

doi:10.1006/bbrc.1999.0394

Cited by 8 publications

(8 citation statements)

References 26 publications

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“…Furthermore, insulin resistance is known to serve an important role in tumor cachexia. A study by Yoshikawa et al (20) demonstrated that insulin resistance in tumor-tolerant mice was due to a decrease in the expression of GLUT-4.…”

Section: Discussionmentioning

confidence: 99%

High developmental pluripotency‑associated 4 expression promotes cell proliferation and glycolysis, and predicts poor prognosis in non‑small‑cell lung cancer

Wang

et al. 2019

Mol Med Report

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The developmental pluripotency-associated 4 (Dppa4) gene serves critical roles in cell self-renewal, as well as in cancer development and progression. However, the regulatory role of Dppa4 in non-small-cell lung cancer (NSCLC) and its underlying mechanisms remain elusive. The aim of the present study was to investigate the biological function of Dppa4 in NSCLC and its underlying mechanism of action. Dppa4 expression was measured in NSCLC tissue samples and cell lines, and its effect on cell proliferation and the expression of glycolytic enzymes was determined. In addition, the underlying mechanisms of Dppa4-induced alterations in glycolysis were analyzed. Univariate and multivariate analyses were also performed to analyze the prognostic significance of clinicopathological characteristics. Dppa4 was found to be highly expressed in NSCLC tissues and cell lines. Furthermore, it was observed that Dppa4 was correlated with the degree of tumor differentiation and TNM stage. Univariate and multivariate analyses identified Dppa4 expression and clinical stage as prognostic factors for NSCLC patients. Kaplan-Meier analysis further revealed that patients with lower Dppa4 expression exhibited a better prognosis. In NSCLC cells, Dppa4 knockdown inhibited cell proliferation, while Dppa4 overexpression enhanced cell proliferation, which was likely mediated by glycolysis promotion. Dppa4 knockdown had no evident effect on the majority of enzymes examined; however, glucose transporter type 4 (GLUT-4) and pyruvate kinase isozyme M2 were significantly upregulated, and hexokinase II (HK-II) and lactate dehydrogenase B (LDHB) were downregulated following Dppa4 knockdown. By contrast, Dppa4 overexpression resulted in downregulation of GLUT-4, and upregulation of HK-II, enolase and LDHB, whereas it had no effect on other enzymes. Since the most evident effect was observed on LDHB, further functional experiments demonstrated that this enzyme reversed the promoting effects of Dppa4 in NSCLC. In conclusion, Dppa4 promotes NSCLC progression, partly through glycolysis by LDHB. Thus, the Dppa4-LDHB axis critically contributes to glycolysis in NSCLC cells, thereby promoting NSCLC development and progression.

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Section: Discussionmentioning

confidence: 99%

High developmental pluripotency‑associated 4 expression promotes cell proliferation and glycolysis, and predicts poor prognosis in non‑small‑cell lung cancer

Wang

et al. 2019

Mol Med Report

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“…Reduced insulin sensitivity is commonly present in both human and animal models of cancer cachexia (Agustsson et al, 2011;Asp et al, 2010: Yoshikawa et al, 2001) and may contribute to muscle wasting via reduced anabolic signaling in response to a meal (Cuthbertson et al, 2005). This state of insensitivity may relate to reduced GLUT4 protein expression in both basal and insulin-stimulated states, due to selective inhibition of insulin-stimulated phosphorylation of IRS1 (Yoshikawa et al, 1999). Possible mediators include proinflammatory cytokines (McCall et al, 1992), central melanocortin signaling (Parton et al, 2007), leptin (Smiechowska et al, 2010), and elevated levels of free fatty acids from mobilized lipid reserves (Zechner et al, 2012).…”

Section: Myostatin and Activinmentioning

confidence: 99%

Cancer Cachexia: Mediators, Signaling, and Metabolic Pathways

2012

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Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies.

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“…Acute insulin resistance is mediated, at least in part, by the action of pro-inflammatory cytokines that are produced during infection, physical trauma, or cancer (2)(3)(4). Chronic insulin resistance is an inevitable consequence of genetic variation that is exacerbated by aging and obesity and contributes to multiple disorders, including glucose intolerance, hyperlipidemia, hypertension and cardiovascular mortality, infertility and polycystic ovarian syndrome, and type II diabetes (5,6).…”

mentioning

confidence: 99%

Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin Receptor and Inhibits Insulin Action

Aguirre

Werner

Giraud

et al. 2002

Journal of Biological Chemistry

869

670

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Inhibition of IRS-1 Phosphorylation and the Alterations of GLUT4 in Isolated Adipocytes from Cachectic Tumor-Bearing Rats

Cited by 8 publications

References 26 publications

High developmental pluripotency‑associated 4 expression promotes cell proliferation and glycolysis, and predicts poor prognosis in non‑small‑cell lung cancer

High developmental pluripotency‑associated 4 expression promotes cell proliferation and glycolysis, and predicts poor prognosis in non‑small‑cell lung cancer

Cancer Cachexia: Mediators, Signaling, and Metabolic Pathways

Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin Receptor and Inhibits Insulin Action

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