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Open Access Highly Accessed Research article

A selenosemicarbazone complex with copper efficiently down-regulates the 90-kDa heat shock protein HSP90AA1 and its client proteins in cancer cells

Hongtao Shen1, Haichuan Zhu25, Mowei Song1, Yonglu Tian3, Yafei Huang2, Hui Zheng4, Ruiyuan Cao2, Jian Lin5, Zhenggang Bi1* and Wu Zhong2*

Author Affiliations

1 The First Affiliated Hospital of Harbin Medical University, Harbin, China

2 Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing, China

3 Laboratory Animal Centre, Peking University, Beijing, China

4 Center for Human Disease Genomics, Peking University, Beijing, China

5 Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China

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BMC Cancer 2014, 14:629  doi:10.1186/1471-2407-14-629

Published: 29 August 2014

Abstract

Background

The 90-kDa heat shock protein HSP90AA1 is critical for the stability of several proteins that are important for tumor progression and thus, is a promising target for cancer therapy. Selenosemicarbazone metal complexes have been shown to possess anticancer activity through an unknown molecular mechanism.

Methods

The MTT assay, fluorescence-activated cell sorting, and fluorescent microscopy were used to analyze the mechanism of the anti-cancer activity of the selenosemicarbazone metal complexes. Additionally, RNA-seq was applied to identify transcriptional gene changes, and in turn, the signaling pathways involved in the process of 2-24a/Cu-induced cell death. Last, the expression of HSP90AA1, HSPA1A, PIM1, and AKT proteins in 2-24a/Cu-treated cells were investigated by western blot analysis.

Results

A novel selenosemicarbazone copper complex (2-24a/Cu) efficiently induced G2/M arrest and was cytotoxic in cancer cells. 2-24a/Cu significantly induced oxidative stress in cancer cells. Interestingly, although RNA-seq revealed that the transcription of HSP90AA1 was increased in 2-24a/Cu-treated cells, western blotting showed that the expression of HSP90AA1 protein was significantly decreased in these cells. Furthermore, down-regulation of HSP90AA1 led to the degradation of its client proteins (PIM1 and AKT1), which are also cancer therapy targets.

Conclusion

Our results showed that 2-24a/Cu efficiently generates oxidative stress and down-regulates HSP90AA1 and its client proteins (PIM1, AKT1) in U2os and HeLa cells. These results demonstrate the potential application of this novel copper complex in cancer therapy.

Keywords:
Selenosemicarbazone; Cell death; Oxidative stress; RNA-seq; HSP90AA1 protein; PIM1; AKT1