G6PD promotes cell proliferation and dexamethasone resistance in multiple myeloma via increasing anti-oxidant production and activatingWnt/β-catenin pathway

Glucose-6-phosphate dehydrogenase (G6PD) has been noticed for its deficiency causing a series of clinical diseases, however, the role of G6PD in cancer remains elusive. In this study, serum metabolic profiling identified that DHEAS level was higher in newly diagnosed multiple myeloma (MM) patients than in normal people. DHEAS can be converted into an endogenously uncompetitive inhibitor of G6PD known as DHEA. Clinical datasets from GEO showed an increasing expression of G6PD during MM progression, especially in those patients resistant to Dexamethasone (Dexa). We further investigated the oncogenic role of G6PD by using two MM cell lines in vitro and xenograft mouse model in vivo . Elevated G6PD promoted MM cell proliferation, in contrast silencing G6PD with RNAi or inhibitor suppressed MM cell growth and improved the survival of MM model mice. Mechanistically, high G6PD expression enhanced enzymatic generation of anti-oxidant NADPH via pentose phosphate pathway (PPP) and decreased the production of reactive oxygen species (ROS) thus inducing proliferation and Dexa resistance in MM cells. Furthermore, canonical Wnt/β-catenin signaling also participated in regulating G6PD-induced drug resistance and cellular redox level of ROS. Intriguingly, DHEA treatment could enhance the sensitivity of MM cells to Dexa mainly through augmenting cellular oxidative stress. In summary, G6PD enhances the enzymatic anti-oxidant NADPH generation and decreases ROS generation, thus encouraging MM cells resistant to Dexa-induced apoptosis mainly via enzymatic PPP pathway and non-enzymatic Wnt/β-catenin signaling pathway in MM. Targeting G6PD to harness cellular redox may afford a promising new strategy to improve therapeutic effect of MM patients.