| Autor: |
Yayoi Matsumura‐Kimoto, Taku Tsukamoto, Yuji Shimura, Yoshiaki Chinen, Kazuna Tanba, Saeko Kuwahara‐Ota, Yuto Fujibayashi, Daichi Nishiyama, Reiko Isa, Junko Yamaguchi, Yuka Kawaji‐Kanayama, Tsutomu Kobayashi, Shigeo Horiike, Masafumi Taniwaki, Junya Kuroda |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Cancer Medicine, Vol 9, Iss 14, Pp 5185-5199 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
2045-7634 |
| DOI: |
10.1002/cam4.3136 |
| Popis: |
Abstract RSK2 is a serine/threonine kinase downstream signaling mediator in the RAS/ERK signaling pathway and may be a therapeutic target in mantle cell lymphoma (MCL), an almost incurable disease subtype of non‐Hodgkin lymphoma. In this study, serine‐227 (RSK2Ser227) in the N‐terminal kinase domain (NTKD) of RSK2 was found to be ubiquitously active in five MCL‐derived cell lines and in tumor tissues derived from five MCL patients. BI‐D1870, an inhibitor specific to RSK2‐NTKD, caused RSK2Ser227 dephosphorylation, and thereby, induced dose‐dependent growth inhibition via G2/M cell cycle blockade and apoptosis in four of the five cell lines, while one cell line showed only modest sensitivity. In addition, RSK2 gene knockdown caused growth inhibition in the four BI‐D1870‐sensitive cell lines. Comparative gene expression profiling of the MCL‐derived cell lines showed that inhibition of RSK2Ser227 by BI‐D1870 caused downregulation of oncogenes, such as c‐MYC and MYB; anti‐apoptosis genes, such as BCL2 and BCL2L1; genes for B cell development, including IKZF1, IKZF3, and PAX5; and genes constituting the B cell receptor signaling pathway, such as CD19, CD79B, and BLNK. These findings show that targeting of RSK2Ser227 enables concomitant blockade of pathways that are critically important in B cell tumorigenesis. In addition, we found favorable combinatory growth inhibitory effects of BI‐D1870 with inhibitors of BTK (ibrutinib), AKT (ipatasertib), and BCL2 (venetoclax) in cell characteristic‐dependent manners. These results provide a rationale for RSK2Ser227 in the NTKD as a potential therapeutic target in MCL and for future development of a novel bioavailable RSK2 NTKD‐specific inhibitor. |
| Databáze: |
Directory of Open Access Journals |
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