Leelamine Modulates STAT5 Pathway Causing Both Autophagy and Apoptosis in Chronic Myelogenous Leukemia Cells

Simple Summary Autophagy is a cellular mechanism that is essential for removing misfolded proteins and damaged organelles. Moreover, the aberrant activation of signal transducer and activator of transcription 5 (STAT5), which can regulate cellular survival and homeostasis, has been often observed in different malignancies. In this study, we demonstrate that leelamine inhibits the STAT5 phosphorylation while inducing autophagy as well as apoptosis in chronic myeloid leukemia cells. Leelamine induces autophagy by stimulating the expression of Atg7, beclin-1, and the production of autophagosomes, which leads to substantial inhibition of STAT5 activation. Leelamine (LEE) has recently attracted significant attention for its growth inhibitory effects against melanoma, breast cancer, and prostate cancer cells; however, its impact on hematological malignancies remains unclear. Here, we first investigate the cytotoxic effects of LEE on several human chronic myeloid leukemia (CML) cells. We noted that LEE stimulated both apoptosis and autophagy in CML cells. In addition, the constitutive activation of signal transducer and activator of transcription 5 (STAT5) was suppressed substantially upon LEE treatment. Moreover, STAT5 knockdown with small interfering RNA (siRNA) increased LEE-induced apoptosis as well as autophagy and affected the levels of various oncogenic proteins. Thus, the targeted mitigation of STAT5 activation by LEE can contribute to its diverse anticancer effects by enhancing two distinct cell death pathways.

Automated summary

In this study, we demonstrate that leelamine inhibits STAT5 activation and induces autophagy and apoptosis in chronic myeloid leukemia cells. This suggests that targeted inhibition of STAT5 by leelamine can enhance two distinct cell death pathways.