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.
Keywords:
CKS1B; ERK1/2; Myeloma; STAT3; and drug resistance.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / pharmacology
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Boronic Acids / pharmacology
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Bortezomib
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CDC2-CDC28 Kinases
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism*
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Drug Resistance, Neoplasm*
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Janus Kinase 1 / antagonists & inhibitors
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Janus Kinase 1 / metabolism*
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase 1 / genetics
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MAP Kinase Kinase 1 / metabolism*
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Pyrazines / pharmacology
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RNA, Small Interfering / genetics
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / metabolism*
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Signal Transduction / drug effects
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Boronic Acids
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CKS1B protein, human
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Carrier Proteins
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Pyrazines
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RNA, Small Interfering
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STAT3 Transcription Factor
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STAT3 protein, human
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Bortezomib
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JAK1 protein, human
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Janus Kinase 1
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CDC2-CDC28 Kinases
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Cyclin-Dependent Kinases
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human