CSNK1?1 mediates malignant plasma cell survival.

ABSTRACT: Here we report that targeting casein kinase 1-?1 (CSNK1?1) is a potential novel treatment strategy in multiple myeloma (MM) therapy distinct from proteasome inhibition. CSNK1?1 is expressed in all the tested MM cell lines and patient MM cells, and is not altered during bortezomib-triggered cytotoxicity. Inhibition of CSNK1?1 kinase activity in MM cells with targeted therapy D4476 or small hairpin RNAs triggers cell G0/G1-phase arrest, prolonged G2/M phase and apoptosis. D4476 also induced cytotoxicity in bortezomib-resistant MM cells and enhanced bortezomib-triggered cytotoxicity. CSNK1?1 signaling pathways include CDKN1B, P53 and FADD; gene signatures involved included interferon-?, tumor necrosis factor-? and LIN9. In addition, reduction of Csnk1?1 prevents cMYC/KRAS12V transformation of BaF3 cells independent of interleukin-3. Impartially, reducing Csnk1?1 prevented development of cMYC/KRAS12V-induced plasmacytomas in mice, suggesting that CSNK1?1 may be involved in MM initiation and progression. Our data suggest that targeting CSNK1?1, alone or combined with bortezomib, is a potential novel therapeutic strategy in MM. Moreover, inhibition of CSNK1?1 may prevent the progression of monoclonal gammopathy of undetermined significance to MM.

SUBMITTER: Hu Y 

PROVIDER: S-EPMC4276736 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature