American journal of cancer research

Bitterness in sugar: O-GlcNAcylation aggravates pre-B acute lymphocytic leukemia through glycolysis via the PI3K/Akt/c-Myc pathway.

PMID 28670495


Abnormal cellular energetics has emerged as a hallmark of cancer cells. Deregulating aerobic glycolysis can alter multiple metabolic and signaling pathways in cancer cells, and trigger unlimited growth and proliferation. Accumulating evidence suggests that elevated levels of protein modification with β-N-acetylglucosamine (O-GlcNAcylation) along with dysregulation of O-GlcNAc transferase (OGT) and/or O-GlcNAcase (OGA) levels may act as a nutrient sensor in cancer cells. However, the underlying mechanism of O-GlcNAcylation and the relationship between O-GlcNAcylation and glycolysis are largely unknown in pre-B acute lymphocytic leukemia (pre-B-ALL). In this study, CD19(+) bone marrow mononuclear cells (BM-MNCs) from untreated pre-B-ALL patients displayed increased O-GlcNAcylation levels, upregulated OGT, and downregulated OGA. Patients with higher lactate dehydrogenase (LDH) levels exhibited higher O-GlcNAcylation levels with OGT upregulation and overactivation of the PI3K/Akt/c-Myc pathway. The extracellular acidification rate (ECAR) and the mRNA expression of key enzymes in glycolysis were determined to assess glycolysis activation. Our results revealed the existence of abnormal glycolysis in the CD19(+) BM-MNCs of pre-B-ALL patients. The knockdown of OGT decreased the ECAR and downregulated glycolysis-related enzymes in Nalm-6 cells via the PI3K/Akt/c-Myc pathway. The suppression of OGT slowed the rate of proliferation and induced apoptosis in Nalm-6 cells. The glycolysis inhibitor 2-deoxy-D-glucose induced cytotoxicity of Nalm-6 cells, which was potentiated by OGT-siRNA. These findings suggested that O-GlcNAcylation could be a hallmark of pre-B-ALL, which has considerable therapeutic potential in clinical practice.

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