Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance
| Autor: | Siqing Wang, Hongwei Xu, Chunjiao Xu, Guido Tricot, Fang Xiao, Lei Shi, Thai M. Cao, Yong Wu, Yinghong Liu, Mohamed E. Salama, Guiyuan Li, Ye Yang, Fenghuang Zhan, Maurizio Zangari |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
STAT3 Transcription Factor
MAPK/ERK pathway Programmed cell death Cell MAP Kinase Kinase 1 Antineoplastic Agents Myeloma Biology Bortezomib STAT3 03 medical and health sciences 0302 clinical medicine Cyclin-dependent kinase CDC2-CDC28 Kinases Tumor Cells Cultured medicine Humans RNA Small Interfering Extracellular Signal-Regulated MAP Kinases 030304 developmental biology 0303 health sciences Gene knockdown drug resistance ERK1/2 Janus kinase 1 Janus Kinase 1 Boronic Acids Cyclin-Dependent Kinases Cell biology Gene Expression Regulation Neoplastic CKS1B medicine.anatomical_structure Oncology Drug Resistance Neoplasm Pyrazines 030220 oncology & carcinogenesis Cancer research biology.protein Signal transduction Carrier Proteins Multiple Myeloma Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | Received: April 28, 2010 , Accepted: April 30, 2010 , Published: May 15, 2010 // Here we demonstrate the crucial role of CKS1B in multiple myeloma (MM) progression and define CKS1B-mediated SKP2/p27Kip1-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 p27Kip1 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. |
| Databáze: | OpenAIRE |
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