Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance |
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Authors: | Shi Lei Wang Siqing Zangari Maurizio Xu Hongwei Cao Thai M Xu Chunjiao Wu Yong Xiao Fang Liu Yinghong Yang Ye Salama Mohamed Li Guiyuan Tricot Guido Zhan Fenghuang |
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Affiliation: | Division of Hematology/BMT/myeloma Program, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA. |
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Abstract: | Here we demonstrate the crucial role of CKS1B in multiple myeloma (MM) progression and define CKS1B-mediated SKP2/p27(Kip1)-independent down-stream signaling pathways. Forced-expression of CKS1B in MM cells increased cell multidrug-resistance. CKS1B activates STAT3 and MEK/ERK pathways. In contrast, SKP2 knockdown or p27(Kip1) over-expression resulted in activation of the STAT3 and MEK/ERK pathways. Further investigations showed that BCL2 is a downstream target of MEK/ERK signaling. Stimulation of STAT3 and MEK/ERK signaling pathways partially abrogated CKS1B knockdown induced MM cell death and growth inhibition. Targeting STAT3 and MEK/ERK signaling pathways by specific inhibitors induced significant MM cell death and growth inhibition in CKS1B-overexpressing MM cells and their combinations resulted in synergy. Thus, our findings provide a rationale for targeting STAT3 and MEK/ERK/BCL2 signaling in aggressive CKS1B-overexpressing MM. |
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Keywords: | Myeloma CKS1B ERK1/2 STAT3 drug resistance |
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