Cyclin-dependent kinase 1 and survivin as potential therapeutic targets against nasal natural killer/T-cell lymphoma
| Autor: | Toshihiro Nagato, Miki Takahara, Shohei Harabuchi, Kan Kishibe, Seigo Ueda, Takumi Kumai, Michele Bernasconi, Kenzo Ohara, Yui Hirata-Nozaki, Hiroya Kobayashi, Yasuaki Harabuchi, Yuki Komabayashi, David Nadal, Takayuki Ohkuri, Ryusuke Hayashi |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Survivin Nose Neoplasms Mice SCID Biology Lymphoma T-Cell Pathology and Forensic Medicine Viral Matrix Proteins 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Mice Inbred NOD Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols CDC2 Protein Kinase medicine Animals Humans Molecular Biology Mice Knockout Gene knockdown Cyclin-dependent kinase 1 Kinase Plicamycin Cell Biology Middle Aged Natural killer T cell medicine.disease Xenograft Model Antitumor Assays Lymphoma Killer Cells Natural 030104 developmental biology Cell culture 030220 oncology & carcinogenesis Cancer research Female RNA Interference biological phenomena cell phenomena and immunity |
| Zdroj: | Laboratory Investigation. 99:612-624 |
| ISSN: | 0023-6837 |
| DOI: | 10.1038/s41374-018-0182-9 |
| Popis: | Nasal natural killer/T-cell lymphoma (NNKTL) is closely associated with Epstein-Barr virus (EBV) and is characterized by poor prognosis, resulting from rapid progression of lesions in the affected organs. Recent data have shown that NNKTL is associated with the aberrant expression of cyclin-dependent kinase 1 (CDK1) and its downstream target survivin, but little is known about the functional roles of CDK1 and survivin in NNKTL. In the current study, we show that knockdown of the EBV-encoded oncoprotein latent membrane protein 1 (LMP1) induces downregulation of CDK1 and survivin in NNKTL cells. Immunohistochemistry detected CDK1 and survivin expression in LMP1-positive cells of NNKTL biopsy specimens. Inhibition of CDK1 and survivin in NNKTL cells with several inhibitors led to a dose-dependent decrease in cell proliferation. In addition, the Sp1 inhibitor mithramycin, which can downregulate both CDK1 and survivin, significantly suppressed the growth of established NNKTL in a murine xenograft model. Our results suggest that LMP1 upregulation of CDK1 and survivin may be essential for NNKTL progression. Furthermore, targeting CDK1 and survivin with Sp1 inhibitors such as mithramycin may be an effective approach to treat NNKTL, which is considered to be a treatment-refractory lymphoma. |
| Databáze: | OpenAIRE |
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