Over-expression of CKS1B activates both MEK/ERK and JAK/ STAT3 signaling pathways and promotes myeloma cell drugresistance

Lei Shi, S. Wang, Maurizio Zangari, Hongwei Xu, Thai M. Cao, Chunjiao Xu, Yong Wu, Fang Xiao, Yinghong Liu, Ye Yang, Mohamed Salama, Guiyuan Li, Guido Tricot, Fenghuang Zhan

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)22-33
Number of pages12
JournalOncotarget
Volume1
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

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Mitogen-Activated Protein Kinase Kinases
Multiple Myeloma
MAP Kinase Signaling System
Cell Death
Multiple Drug Resistance
Growth

Keywords

  • And drug resistance
  • CKS1B
  • ERK1/2
  • Myeloma
  • STAT3

ASJC Scopus subject areas

  • Oncology

Cite this

Over-expression of CKS1B activates both MEK/ERK and JAK/ STAT3 signaling pathways and promotes myeloma cell drugresistance. / Shi, Lei; Wang, S.; 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.

In: Oncotarget, Vol. 1, No. 1, 01.01.2010, p. 22-33.

Research output: Contribution to journalArticle

Shi, L, Wang, S, Zangari, M, Xu, H, Cao, TM, Xu, C, Wu, Y, Xiao, F, Liu, Y, Yang, Y, Salama, M, Li, G, Tricot, G & Zhan, F 2010, 'Over-expression of CKS1B activates both MEK/ERK and JAK/ STAT3 signaling pathways and promotes myeloma cell drugresistance', Oncotarget, vol. 1, no. 1, pp. 22-33. https://doi.org/10.18632/oncotarget.105
Shi, Lei ; Wang, S. ; 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. / Over-expression of CKS1B activates both MEK/ERK and JAK/ STAT3 signaling pathways and promotes myeloma cell drugresistance. In: Oncotarget. 2010 ; Vol. 1, No. 1. pp. 22-33.
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