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WAVE1 regulates P-glycoprotein expression via Ezrin in leukemia cells

'WAVE1 regulates P-glycoprotein expression via Ezrin in leukemia cells'
ORIGINAL ARTICLE: RESEARCH WAVE1 regulates P-glycoprotein expression via Ezrin in leukemia cells MING-HUA YANG1, MING-YI ZHAO1, ZHUO WANG1, RUI KANG1,4, YU-LEI HE2, XIAO-CHENG YIN3, LI-YING LIU1, LIANG-CHUN YANG1, CAI-XIA ZHAN1, XIU-SHAN WU5, DAO-LIN TANG4, revised 1 November 2010; accepted 4 November 2010) Abstract For children with acute myeloblastic leukemia (AML), multidrug resistance (MDR) reduces treatment effectiveness, and often leads to poor patient survival. While a number of factors have been described that affect MDR, the mechanisms underlying this effect remain unclear. In this study, the role of WAVE1 in MDR was investigated. Among 62 children with AML, high levels of WAVE1 were associated with poor patient outcomes. Proteomic techniques were used to identify novel WAVE1-interacting proteins from leukemia cells, one of which was the cytoskeleton regulator Ezrin. In leukemia cells, WAVE1 co-localized with both Ezrin and P-glycoprotein (P-gp), a critical regulator of the MDR phenotype. Overexpression of WAVE1 in K562 leukemia cells up-regulated P-gp and Ezrin, and reduced K562 cells’ sensitivity to the chemotherapy drug adriamycin. The opposite effect was seen when WAVE1 expression was reduced via RNA interference. Critically, overexpression of WAVE1 in the absence of Ezrin did not affect P-gp levels or MDR. These data suggest that WAVE1 affects P-gp and MDR of leukemia cells through Ezrin. Keywords: WAVE1, drug resistance, Ezrin, P-glycoprotein Introduction The Wiskott–Aldrich syndrome family of proteins, including WAVE1, WAVE2, WAVE3, WASP, and N-WASP, transduces signals from transmembrane receptors to the actin cytoskeleton [1]. Cytoskeleton regulation is essential for a myriad of cellular processes, including cell motility, morphogenesis, and apoptotic cell death [2]. WAVE1 is expressed most abundantly in murine brain tissue, but low levels of expression are also found in tissues such as the heart, liver, lung, kidney, pancreas, and periph- eral blood [3]. Essential for central nervous system development and mammalian fertilization [4–6], WAVE1 also interacts with mitochondrial proteins (i.e. glucokinase and protein kinase A). In this way, WAVE1 coordinates cell death and glycolysis [7]. We have previously demonstrated that WAVE1 is overexpressed in blood cancer cell lines, and in this context functions as a negative regulator of apoptosis [8]. Based on fi ndings such as these, we analyzed WAVE1 expression in children with acute myelo- blastic leukemia (AML). Evidence suggests that high levels of WAVE1 in patient bone marrow correlate with unfavorable prognoses [9]. Finally, we have shown that WAVE1 is involved in multidrug resis- tance (MDR) of K562/A02 leukemia cells [10]. These fi ndings support a general role for WAVE1 in the regulation of drug resistance and AML pathogenicity. P-glycoprotein (P-gp)/Mdr1 is a 170 kDa glycosy- lated integral plasma membrane protein, belonging Correspondence: Li-Zhi Cao, Department of Pediatrics
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WAVE1regulatesP-glycoproteinexpressionviaEzrininleukemiacells
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