Hyper-O-GlcNAcylation Is Anti-apoptotic and Maintains Constitutive NF-κB Activity in Pancreatic Cancer Cells

Abstract

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.

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

“…Consequently, cancer cell metabolic changes, including increased glucose uptake due to the Warburg effect and increased glutamine uptake, likely cooperate to drive increased HBP flux. In support of this, we found that the end products of the HBP (including UDP-GlcNAc) are elevated in pancreatic cancer cells (15). Thus, it appears that increased HBP flux and elevated UDPGlcNAc are general features of cancer cells that contribute to hyper-O-GlcNAcylation.…”

“…Indeed, we found that reducing hyper-O-GlcNAcylation in the pancreatic ductal adenocarcinoma cell lines MiaPaCa-2 and PANC-1 decreases the expression of the anti-apoptotic protein Bcl-x L and induces pro-apoptotic cleavage of caspase-9 and caspase-3. These results indicate that reducing pancreatic cancer cell hyper-O-GlcNAcylation triggers the intrinsic apoptotic pathway (15). Conversely, increasing O-GlcNAc in pancreatic cancer BxPC-3 cells protects against suspension-induced apoptosis (15).…”

“…Cyclin D 1 is a positive regulator of the G 1 /S transition. Recent work with different cancer types has shown that reducing cancer cell hyper-O-GlcNAcylation either genetically or pharmacologically attenuates the expression of cyclin D 1 (15,49,50). Thus, cancer cell hyper-OGlcNAcylation appears to contribute in part to excessive growth through up-regulation of key proteins that drive cell cycle progression such as cyclin D 1 and down-regulation of cell cycle inhibitory proteins such as p27…”

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

“…As a nutrient sensor, O-GlcNAc relays the effects of excessive nutritional intake, an important cancer risk factor, onto protein activities and cellular functions (8). Indeed, major tumor suppressors and oncoproteins, such as p53, MYC, NF-κB, and β-catenin are direct targets of O-GlcNAc (12)(13)(14)(15)(16)(17). Chromatin dynamics is also modulated by O-GlcNAc.…”

“…cancers (16,19,20), but neither has been examined previously in the context of HPV oncogene expression or cervical neoplasms. In this work, we asked whether O-GlcNAc might play a role in HPVinduced transformation and carcinogenesis.…”