Abstract
BackgroundAcute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL.MethodsALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model.ResultsALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression.ConclusionsThe present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.
Highlights
Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children
ALT inhibits the proliferation of ALL cells To investigate the potential effects of ALT on ALL, ALL cell lines, including BV173, JM-1, NALM1, NALM6, RS6, and SUPB1, were treated with 1, 5 and 10 μM of ALT for 24 h
Cell viability was determined using an ALT treatment increases expression of AP2M1 To elucidate the mechanism underlying the effects of ALT on ALL cells, we screened the mRNA expression profiles of cells using RNA-seq
Summary
Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. ALT has been reported to exert anti-tumor effects in several types of cancer, including lung cancer, gastric cancer, hepatic cancer, B cell acute lymphoblastic leukemia, pancreatic cancer and breast cancer [8]. Wang et al reported that ALT could enhance the sensitivity of lung cancer cells to gemcitabine [9]. ALT enhances the sensitivity of cancer cells to EGFR inhibitors through inhibition of STAT3 signaling [11]. These pathways are overlapping and interact with each other. The role and molecular mechanisms of ALT in ALL remain unexplored
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