Glycolytic enzyme hexokinase II is a putative therapeutic target in B cell malignant lymphoma.

Hexokinase II (HXKII) is a key regulator of glucose metabolism that converts glucose to glucose-6-phosphate. Furthermore, HXKII blocks mitochondria-dependent apoptosis by inhibiting the release of cytochrome c. HXKII overexpression is frequently found in several types of cancer and confers chemoresistance to cancer cells. In the present study, we revealed that compared to cell lines generated from diffuse large B cell lymphoma (DLBCL) patients, cell lines with features of Burkitt lymphoma have higher levels of HXKII due to activation of both c-MYC and HIF-1. Under normoxia, HXKII levels were correlated with the growth ability of each B cell lymphoma cell line. HXKII levels were further enhanced when the B cell lymphoma cells were cultured under hypoxia. The high levels of HXKII induced by hypoxia conferred cisplatin resistance in all tested B cell lymphoma cell lines. The histone deacetylase (HDAC) inhibitor panobinostat significantly suppressed HXKII expression under both normoxic and hypoxic conditions. Importantly, panobinostat reversed the anti-lymphoma action of cisplatin, and this effect was diminished by hypoxia. These data suggest that HXKII plays different roles, including in the regulation of glycolysis and inhibition of apoptosis, depending on its expression levels. Furthermore, inhibition of HXKII expression by panobinostat may represent a new and attractive strategy to overcome cisplatin resistance.