Cinobufagin suppresses T-ALL via USP7-Mediated inhibition of NOTCH1/PI3K signaling pathways

T-cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous disease which has low survival rate and liable to recurrence. Cinobufagin (CBG) is an active ingredient extracted from traditional Chinese medicine ChanSu, which exerts inhibitory effect in various cancers. However, the therapeutic effect of CBG on T-ALL remains still unknown. This study demonstrated that CBG induced Apoptosis in T-ALL cells by activating Caspase-3 signaling pathway and concurrently arrested the cell cycle of T-ALL cells. Mechanistically, Ubiquitin-Specific Protease 7 (USP7) was shown to be overexpressed in T-ALL cells, and USP7 knockdown induced Apoptosis in Jurkat cells. Moreover, knockdown of USP7 resulted in the blockage of NOTCH1 and PI3K pathways. Cellular thermal shift assay (CESTA) and molecular docking demonstrated that CBG suppressed the abnormal activation of USP7 in T-ALL cells, further interrupting the NOTCH1 and Phosphatidylinositol-3 kinase (PI3K) pathways. Furthermore, the overexpression of USP7 in Jurkat xenograft mice promoted the pathenogenesis of T-ALL. CBG displayed therapeutic effect by inhibiting the expression of USP7, without inducing significant liver damage. Overall, this study demonstrated that CBG induced Apoptosis of T-ALL cells by targeting USP7 and further regulating NOTCH1/PI3K pathways.

Cancer therapy; Cinobufagin; NOTCH1 pathway; PI3K pathway; T-cell acute lymphoblastic leukemia; USP7.