ADP-dependent glucokinase as a novel onco-target for haematological malignancies

Abstract

Warburg effect or aerobic glycolysis provides selective growth advantage to aggressive cancers. However, targeting oncogenic regulators of Warburg effect has always been challenging owing to the wide spectrum of roles of these molecules in multitude of cells. In this study, we present ADP-dependent glucokinase (ADPGK) as a novel glucose sensor and a potential onco-target in specifically high-proliferating cells in Burkitt’s lymphoma (BL). Previously, we had shown ADPGK to play a major role in T-cell activation and induction of Warburg effect. We now report ADPGK knock-out Ramos BL cells display abated in vitro and in vivo tumour aggressiveness, via tumour-macrophage co-culture, migration and Zebrafish xenograft studies. We observed perturbed glycolysis and visibly reduced markers of Warburg effect in ADPGK knock-out cells, finally leading to apoptosis. We found repression of MYC proto-oncogene, and up to four-fold reduction in accumulated mutations in translocated MYC in knock-out cells, signifying a successful targeting of the malignancy. Further, the activation induced differentiation capability of knock-out cells was impaired, owing to the inability to cope up with increased energy demands. The effects amplified greatly upon stimulation-based proliferation, thus providing a novel Burkitt’s lymphoma targeting mechanism originating from metabolic catastrophe induced in the cells by removal of ADPGK.