Journal
ONCOTARGET
Volume 1, Issue 1, Pages 22-33Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.105
Keywords
Myeloma; CKS1B; ERK1/2; STAT3; drug resistance
Categories
Funding
- National Institutes of Health [RO1 CA115399]
- University of Utah
- Multiple Myeloma Research Foundation
- NATIONAL CANCER INSTITUTE [R01CA152105, R01CA115399] Funding Source: NIH RePORTER
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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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