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Abstract
IntroductionN-myc downstream-regulated gene 2 (NDRG2), a novel tumour suppressor and cell stress-related gene, is involved in many cell metabolic processes, such as hormone, ion and fluid metabolism. We investigated whether NDRG2 is involved in any glucose-dependent energy metabolism, as well as the nature of its correlation with breast carcinoma.MethodsThe correlations between NDRG2 expression and glucose transporter 1 (GLUT1) expression in clinical breast carcinoma tissues were analysed. The effects of NDRG2 on glucose uptake were assessed in breast cancer cells and xenograft tumours. The consequences of NDRG2-induced regulation of GLUT1 at the transcription and translation levels and the interaction between NDRG2 and GLUT1 were examined.ResultsData derived from clinical breast carcinoma specimens revealed that (1) patients with high NDRG2 expression had better disease-free survival and overall survival than those with low NDRG2 expression and (2) NDRG2 expression was negatively correlated with GLUT1 expression in these breast carcinoma tissues. NDRG2 inhibited glucose uptake by promoting GLUT1 protein degradation without affecting GLUT1 transcription in both breast cancer cells and xenograft tumours. In addition, NDRG2 protein interacted and partly colocalised with GLUT1 protein in cell cytoplasm areas.ConclusionsThe results of our study support the notion that NDRG2 plays an important role in tumour glucose metabolism, in which GLUT1 is a likely candidate contributor to glucose uptake suppression and tumour growth. Targeting the actions of NDRG2 in cell glucose-dependent energy delivery may provide an attractive strategy for therapeutic intervention in human breast carcinoma.
Highlights
N-myc downstream-regulated gene 2 (NDRG2), a novel tumour suppressor and cell stress-related gene, is involved in many cell metabolic processes, such as hormone, ion and fluid metabolism
Relationship between NDRG2 expression and clinical histopathological characteristics in breast carcinoma To assess the significance of NDRG2 protein expression in the development and progression of breast cancer, we compared the histopathological characteristics of 269 breast cancer samples with available NDRG2 protein status
The results show that patients with high NDRG2 expression in breast tumour tissues had better disease-free survival than those with low NDRG2 expression (P = 0.0066 by logrank test) (Figure 1A)
Summary
N-myc downstream-regulated gene 2 (NDRG2), a novel tumour suppressor and cell stress-related gene, is involved in many cell metabolic processes, such as hormone, ion and fluid metabolism. Accumulating evidence indicates that NDRG2 is a tumour suppressor gene that is downregulated or undetectable in many human cancers [1,3]. In addition to its known antitumoural function, NDRG2 may be a metabolism-related gene regulated by many hormones, including adrenal steroids [7], dexamethasone [8,9], insulin [10,11,12], androgen [13], oestrogen [14] and aldosterone [15]. We identified that NDRG2 acted as a key molecule in pancreatic β cells and was involved in Akt-mediated protection of β cells against lipotoxicity [11]. Very little information is available regarding the function of NDRG2 in tumour metabolism
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