Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells

Molecular Cancer

Research

Zhengjia Chen¹  Songqing Fan²  Fray F Marshall³  Ruoxiang Wang³  Daqing Wu³  Shareen Iqbal³  Shumin Zhang³  Adeboye O Osunkoya⁴  Leland WK Chung⁵  Haiyen E Zhau⁵  Xiaojian Yang⁶ 

[1] Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA;Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, China;Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA;Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA;Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA;Uro-Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA;Uro-Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China;

关键词: Vascular Endothelial Growth Factor;    Hepatocyte Growth Factor;    NRP1 Expression;    Hepatocyte Growth Factor Treatment;    Vascular Endothelial Growth Factor Induction;   

DOI  :  10.1186/1476-4598-9-9

 received in 2009-08-13, accepted in 2010-01-19,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundMyeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family, which inhibits cell apoptosis by sequestering pro-apoptotic proteins Bim and Bid. Mcl-1 overexpression has been associated with progression in leukemia and some solid tumors including prostate cancer (PCa). However, the regulatory mechanism for Mcl-1 expression in PCa cells remains elusive.ResultsImmunohistochemical analyses revealed that Mcl-1 expression was elevated in PCa specimens with high Gleason grades and further significantly increased in bone metastasis, suggesting a pivotal role of Mcl-1 in PCa metastasis. We further found that vascular endothelial growth factor (VEGF) is a novel regulator of Mcl-1 expression in PCa cells. Inhibition of endogenous Mcl-1 induced apoptosis, indicating that Mcl-1 is an important survival factor in PCa cells. Neuropilin-1 (NRP1), the "co-receptor" for VEGF165 isoform, was found to be highly expressed in PCa cells, and indispensible in the regulation of Mcl-1. Intriguingly, VEGF165 promoted physical interaction between NRP1 and hepatocyte growth factor (HGF) receptor c-MET, and facilitated c-MET phosphorylation via a NRP1-dependent mechanism. VEGF165 induction of Mcl-1 may involve rapid activation of Src kinases and signal transducers and activators of transcription 3 (Stat3). Importantly, NRP1 overexpression and c-MET activation were positively associated with progression and bone metastasis in human PCa specimens and xenograft tissues.ConclusionsThis study demonstrated that Mcl-1 overexpression is associated with PCa bone metastasis. Activation of VEGF165-NRP1-c-MET signaling could confer PCa cells survival advantages by up-regulating Mcl-1, contributing to PCa progression.

【 授权许可】

Unknown   
© Zhang et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.