Regulating TKT activity inhibits proliferation of human acute lymphoblastic leukemia cells

Abstract

Abstract Background Among pediatric blood cancers, acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy. Within ALL, the T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10 to 15% of all pediatric cases, and ~ 25% of adult cases. Their overall survival rate is 80%. The overall prevalence of ALL was 4/100,000 population. In Taiwan, it accounts for 25 to 30% of all childhood cancers and with ~ 200 newly diagnosed cases every year. Its recurrence and relapse after treatment remain problematic. It is therefore the need to develop new therapies for patients with T-ALL. Recent studies suggested regulating energy metabolism is a novel approach to inhibit tumor growth, likely a promising treatment of this cancer. Transketolase (TKT) is an important enzyme for modulating glucose metabolize in the pentose phosphate pathway. Methods Human T-ALL cell lines were treated with different doses of niclosamide and primary T-ALL PBMCs were analyzed by RNA sequencing. Cell viability were analyzed by CCK-8 assay. Human T-ALL cells treated with niclosamide were also conducted for Western blotting analysis and TKT activity assay. Metabolism evaluation of T-ALL cells were analyzed by ATP assay and seahorse analyses. Last, the effect of knockdown TKT on T-ALL tumor growth was examined in a T-ALL xenograft murine model. Tumor samples from T-ALL xenograft murine model were analyzed by hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) staining. Results In our study, we demonstrated that niclosamide reduced cell viability of T-ALL cells, and it also reduced expressions of TKT, TKTL1/2, transaldolase. In addition, niclosamide inhibited TKT enzyme activity, aerobic metabolism and glycolysis, finally leading to reduced ATP production. The tumor growth of xenograft T-ALL mice were inhibited by the knockdown of TKT. Conclusions Findings showed that niclosamide inhibits T-ALL cell growth by inhibiting TKT and energy metabolism.