Hsp90 inhibitor induces KG-1a cell differentiation and apoptosis via Akt/NF-κB signaling.

Abstract

Heat-shock protein 90 (Hsp 90) acts as a molecular chaperone that maintains protein stability and regulates cell proliferation, survival, differentiation and apoptosis. The present study investigated the effect of Hsp90 inhibition on human acute myeloid leukemia (AML) cells using the novel small-molecule inhibitor SNX-2112. We found that SNX-2112 more potently inhibited KG-1a cell growth than the classical Hsp90 inhibitor 17-(2-dimethylaminoethyl)amino‑17-demethoxygeldanamycin as determined by CCK-8 assay. Flow cytometry was used to examine the cell cycle, differentiation, and apoptosis, and western blotting and qRT-PCR were used to analyze the underlying mechanism. The results revealed that low concentrations of SNX-2112 arrested the cells in the G2/M phase and induced their differentiation and apoptosis, possibly by suppressing Akt and inhibitor of κB kinase, a component of the nuclear factor (NF)-κB signaling pathway. We also found that SNX-2112 increased the expression of the differentiation transcription factors PU.1 and CCAAT‑enhancer-binding protein-α. Thus, SNX-2112 induced KG-1a cell differentiation, cell cycle arrest and apoptosis via modulation of Akt and NF-κB signaling, suggesting that it is a promising therapeutic agent for the treatment of AML.

• Authors: Jin-Hong Qin, Kun Wang, Xin-Lu Fu, Peng-Jun Zhou, Zhong Liu, Dan-Dan Xu, Yi-Fei Wang, De-Po Yang, Qiu-Ling Xie, Qiu-Ying Liu
• Journal: Oncology reports (Oncol Rep) Vol. 38 Issue 3 Pg. 1517-1524 (Sep 2017) ISSN: 1791-2431 [Electronic] Greece
• PMID: 28713903 (Publication Type: Journal Article)

Chemical References

• HSP90 Heat-Shock Proteins
• Heterocyclic Compounds, 4 or More Rings
• NF-kappa B
• SNX 2112
• Proto-Oncogene Proteins c-akt

Topics

• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics)
• Heterocyclic Compounds, 4 or More Rings (administration & dosage)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, pathology)
• NF-kappa B (genetics)
• Proto-Oncogene Proteins c-akt (genetics)
• Signal Transduction (drug effects)