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Inhibition of Karyopherin beta 1 suppresses prostate cancer growth

Abstract

Prostate cancer (PCa) initiation and progression requires activation of numerous oncogenic signaling pathways. Nuclear-cytoplasmic transport of oncogenic factors is mediated by Karyopherin proteins during cell transformation. However, the role of nuclear transporter proteins in PCa progression has not been well defined. Here, we report that the KPNB1, a key member of Karyopherin beta subunits, is highly expressed in advanced prostate cancers. Further study showed that targeting KPNB1 suppressed the proliferation of prostate cancer cells. The knockdown of KPNB1 reduced nuclear translocation of c-Myc, the expression of downstream cell cycle modulators, and phosphorylation of regulator of chromatin condensation 1 (RCC1), a key protein for spindle assembly during mitosis. Meanwhile, CHIP assay demonstrated the binding of c-Myc to KPNB1 promoter region, which indicated a positive feedback regulation of KPNB1 expression mediated by the c-Myc. In addition, NF-κB subunit p50 translocation to nuclei was blocked by KPNB1 inhibition, which led to an increase in apoptosis and a decrease in tumor sphere formation of PCa cells. Furthermore, subcutaneous xenograft tumor models with a stable knockdown of KPNB1 in C42B PCa cells validated that the inhibition of KPNB1 could suppress the growth of prostate tumor in vivo. Moreover, the intravenously administration of importazole, a specific inhibitor for KPNB1, effectively reduced PCa tumor size and weight in mice inoculated with PC3 PCa cells. In summary, our data established the functional link between KPNB1 and PCa prone c-Myc, NF-kB, and cell cycle modulators. More importantly, inhibition of KPNB1 could be a new therapeutic target for PCa treatment.

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Acknowledgements

This study was partly supported by NYU CSCB Pilot Study Award to JY, National Institutes of Health grants R01CA180277, R01DE025992 and R01DE027074 to XL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

JY and YG conducted most of the experiments, data acquisition, and manuscript preparation. LL, RZ, YZ, and YW conducted some of the experiments, CL and WY conducted bioinformatics analyses, CJW, CHC, and SO did blind analysis of the IHC images. XL contributes to the conceptual design and manuscript revision.

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Correspondence to Xin Li.

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