Background: Cancer cells rely on energy metabolism that requires increased glucose uptake and constitutive NF-B activity for survival. Results: Pancreatic cancer cells display elevated O-GlcNAcylation, reduction of which inhibits cell survival and oncogenic NF-B signaling. Conclusion: Hyper-O-GlcNAcylation is anti-apoptotic and contributes to NF-B activation in pancreatic cancer. Significance: Targeting hyper-O-GlcNAcylation may serve as a novel therapeutic intervention in pancreatic cancer.
The Hexosamine Biosynthetic Pathway (HBP) is highly dependent on multiple metabolic nutrients including glucose, glutamine and acetyl-CoA. Increased flux through HBP leads to elevated post-translational addition of β-D-N-acetylglucosamine sugars to nuclear and cytoplasmic proteins. Increased total O-GlcNAcylation is emerging as a general characteristic of cancer cells and recent studies suggest that O-GlcNAcylation is a central communicator of nutritional status to control key signaling and metabolic pathways that regulate multiple cancer cell phenotypes. This review summarizes our current understanding of changes of O-GlcNAc cycling enzymes in cancer, the role of O-GlcNAcylation in tumorigenesis and the current challenges in targeting this pathway therapeutically.
O-Linked -N-acetylglucosamine (O-GlcNAc) is a carbohydrate post-translational modification on hydroxyl groups of serine and/or threonine residues of cytosolic and nuclear proteins. Analogous to phosphorylation, O-GlcNAcylation plays crucial regulatory roles in cellular signaling. Recent work indicates that increased O-GlcNAcylation is a general feature of cancer and contributes to transformed phenotypes. In this minireview, we discuss how hyper-O-GlcNAcylation may be linked to various hallmarks of cancer, including cancer cell proliferation, survival, invasion, and metastasis; energy metabolism; and epigenetics. We also discuss potential therapeutic modulation of O-GlcNAc levels in cancer treatment.
It has been reported that sleeve lobectomy (SL) concomitant with or without pulmonary artery reconstruction (PAR) might be an alternative procedure for pneumonectomy (PN) in non-small cell lung cancer (NSCLC). The aim of this study was to assess whether SL or PN offers a low morbidity and mortality and better long-term survival. We performed a meta-analysis of studies published in English between 1996 and 2006 to comprehensively compare the postoperative mortality, morbidity, locoregional recurrences, and time-to-event outcomes of SL and PN in NSCLC, and reviewed the recent literatures on PAR in the corresponding period as well. Twelve studies met the defined criteria including a total of 2984 subjects, and five studies for PAR. The odds ratio for postoperative mortality (SL vs PN) was 0.65 (95% confidence interval (CI): 0.42-1.01), 1.01 (95% CI: 0.70-1.44) for postoperative complications, and 0.91 (95% CI: 0.45-1.82) for locoregional recurrences. The weighted mean operative mortality for PAR was 3.3%, and 32.4% for complications. The estimated combined hazard ratio for overall survival in 10 studies was 0.70 (95% CI: 0.62-0.79) in favor of SL group. The median overall survival was 60 months for the SL group, 26 months for the PN group, and 30 months for PAR group. Survival difference in patients with pN0 or pN1 at 1 year demonstrated a pooled risk difference (SL vs PN) of 0.03 (95% CI: -0.08-0.13), 0.13 (95% CI: 0.00-0.25) in patients with pN2 at 1 year, 0.21 (95% CI: 0.07-0.36) in patients with pN0 or pN1 at 5 years, and 0.06 (95% CI: -0.10-0.21) in patients with pN2 at 5 years. Our results suggests that SL with or without PAR can be accomplished safely in selected patients without increasing the morbidity and mortality as compared to PN, that SL even with PAR offers better long-term survival than does PN, and that a more radical operation such as PN is not a more appropriate procedure, even in higher stage tumors.
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