期刊
LEUKEMIA
卷 28, 期 1, 页码 155-165出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.115
关键词
multiple myeloma (MM); selective inhibitors of nuclear export (SINEs) against CRM1/XPO1; osteoclasts (OC); nuclear factor-kappa B (NF-kappa B) activation; nuclear export protein; tumor suppressors
资金
- National Institutes of Health [RO-1 50947, PO1-78378]
- DF/HCC SPORE in Multiple Myeloma [P50CA100707]
- Lebow Fund
- NATIONAL CANCER INSTITUTE [P01CA078378, P01CA155258, P50CA100707] Funding Source: NIH RePORTER
The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50 <200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor kappa B (NF-kappa B) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-kappa B and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据