Inhibition of Karyopherin beta 1 suppresses prostate cancer growth
| Autor: | Yuqi Guo, Katherine J. Wang, Jian Yang, Liang Luo, Catherine H. Chu, Ruohan Zhang, Yanli Zhang, Cuijie Lu, Sabrine I. Obbad, Yaoyu Wang, Wenbo Yan, Xin Li |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Cancer Research Cell Down-Regulation Mice Nude Biology Article 03 medical and health sciences Prostate cancer Mice 0302 clinical medicine Cell Line Tumor Genetics medicine Animals Humans NF-kB RNA Small Interfering Molecular Biology Mitosis Karyopherin Cell Proliferation chemistry.chemical_classification Gene knockdown Prostatic Neoplasms Cell cycle medicine.disease prostate cancer beta Karyopherins Xenograft Model Antitumor Assays 3. Good health RCC1 Gene Expression Regulation Neoplastic tumorigenesis 030104 developmental biology medicine.anatomical_structure c-Myc chemistry Apoptosis 030220 oncology & carcinogenesis PC-3 Cells Cancer research Quinazolines Beta Karyopherins cell cycle KPNB1 |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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