Cancer cells have accelerated metabolism and high glucose requirements. The up-regulation of specific glucose transporters may represent a key mechanism by which malignant cells may achieve increased glucose uptake to support the high rate of glycolysis. In present study we analyzed the mRNA and protein expression of GLUT1 and GLUT3 glucose transporters by quantitative real-time polymerase chain reaction (Q-PCR) and Western blotting technique in 76 cases of endometrial carcinoma and 70 cases of breast carcinoma. SLC2A1 and SLCA2A3 mRNAs expression was found, respectively in 100% and 97.4% samples of endometrial cancers and only in 50% and 40% samples of breast cancers. In endometrial cancers GLUT1 and GLUT3 protein expression was identified in 67.1% and 30.3% of cases. Analogously, in breast cancers in 48.7% and 21% of samples, respectively. The results showed that both endometrial and breast poorly differentiated tumors (grade 2 and 3) had significantly higher GLUT1 and GLUT3 expression than well-differentiated tumors (grade 1). Statistically significant association was found between SLCA2A3 mRNA expression and estrogen and progesterone receptors status in breast cancers. GLUT1 has been reported to be involved in the uptake of glucose by endometrial and breast carcinoma cells earlier and the present study determined that GLUT3 expression is also involved. GLUT1 and GLUT3 seem to be important markers in endometrial and breast tumors differentiation.
Summary Protein-O-linked N-Acetyl-b-D-glucosaminidase (O-GlcNAcase, OGA; also known as hexosaminidase C) participates in a nutrientsensing, hexosamine signaling pathway by removing O-linked N-acetylglucosamine (O-GlcNAc) from key target proteins. Perturbations in O-GlcNAc signaling have been linked to Alzheimer's disease, diabetes and cancer. Mammalian O-GlcNAcase exists as two major spliced isoforms differing only by the presence (OGA-L) or absence (OGA-S) of a histone-acetyltransferase domain. Here we demonstrate that OGA-S accumulates on the surface of nascent lipid droplets with perilipin-2; both of these proteins are stabilized by proteasome inhibition. We show that selective downregulation of OGA-S results in global proteasome inhibition and the striking accumulation of ubiquitinylated proteins. OGA-S knockdown increased levels of perilipin-2 and perilipin-3 suggesting that O-GlcNAcdependent regulation of proteasomes might occur on the surface of lipid droplets. By locally activating proteasomes during maturation of the nascent lipid droplet, OGA-S could participate in an O-GlcNAc-dependent feedback loop regulating lipid droplet surface remodeling. Our findings therefore suggest a mechanistic link between hexosamine signaling and lipid droplet assembly and mobilization.
O-GlcNAcylation is an abundant, dynamic, and inducible posttranslational modification in which single β-N-acetylglucosamine residues are attached by O-glycosidic linkage to serine or treonine residues. It is suggested that abnormally regulated O-GlcNAcylation may contribute to the pathology of cancer. Cycling of O-GlcNAc residues on intracellular proteins is controlled by two enzymes, O-GlcNAc transferease (OGT), which catalyses the addition of O-GlcNAc residues and nucleocytoplasmic β-N-acetylglucosaminidase (O-GlcNAcase; encoded by MGEA5 gene), an enzyme involved in the removal of O-GlcNAc. In this study, relationship between the mRNA expressions of genes coding O-GlcNAc cycling enzymes in breast ductal carcinomas and clinicopathological parameters were analyzed. The results showed that poorly differentiated tumors (grade II and III) had significantly higher OGT expression than grade I tumors. Contrary, MGEA5 transcript levels were significantly lower in grade II and III in comparison with grade I tumors. The Spearman rank correlation showed the expressions of OGT and MGEA5 in breast cancer was negatively correlated (r = −0.430, P = 0.0002). Lymph node metastasis status was significantly associated with decreased MGEA5 mRNA expression. This result suggests that elevation in O-GlcNAc modification of proteins may be implicated in breast tumor progression and metastasis.
Metallothioneins (MTs) are a family of metal binding proteins that play an important role in cellular processes such as proliferation and apoptosis. Metallothionein 2A is the most expressed MT isoform in the breast cells. A number of studies have demonstrated increased MT2A expression in various human tumors, including breast cancer. We carried out an association study to examine whether MT2A gene polymorphisms are associated with risk of breast cancer. Information on lifestyle risk factors was collected via a self-administered questionnaire. Genotyping was conducted using polymerase chain reaction–restriction fragment length polymorphism technique. Three single nucleotide polymorphisms (SNP) rs28366003, rs1610216 and rs10636 were genotyped in 534 breast cancer cases and 556 population controls. One SNP in MT2A (rs28366003) showed a positive association with breast cancer. Compared with homozygous common allele carriers, heterozygous for the G variant [odds ratio (OR) = 1.92, 95 % confidence interval (CI):1.28–2.81, p trend <0.01; the OR assuming a dominant model 1.93 (95 % CI: 1.29–2.89, pdominant <0.02) after adjustment for age, family history, smoking status, BMI, menarche, parity, menopausal status and use of contraceptive and menopausal hormones] had a significantly increased risk of breast cancer in Polish population, as well as women with haplotypes, including variant allele of rs28366003 SNP (OR = 1.58, CI: 0.41–6.33, p global = 0.03). Our data suggest that the rs28366003 SNP in MT2A is associated with risk of breast cancer in Polish population.
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