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Correspondence: dwu2@emory.edu

SZ performed western blotting, immunoprecipitation, immunofluorescence confocal microscopy, and gene transfer experiments (siRNA and cDNA expression).

HEZ established the ARCaP PCa progression model, provided human PCa tissue specimens, designed and performed the immunohistochemical staining of NRP1 and p-c-MET in ARCaP tumors and human PCa specimens.

AOO provided human PCa tissue specimens and evaluated expression of NRP1 and p-c-MET.

SF evaluated expression of Mcl-1 in PCa tissue microarray specimens.

ZC performed statistical analyses.

XY and SI performed cell culture and preparation of proteins and RNA samples.

RW contributed to the establishment of the ARCaP animal models.

FFM and LWKC participated in discussion and manuscript preparation.

LWKC provided grant supports for this study.

DW designed experiments and drafted manuscript.

All authors read and approved the final version of this manuscript.

The authors declare that they have no competing interests.

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Research Funding:

This study was supported by Department of Defense PC060566, Georgia Cancer Coalition Cancer Research Award and National Cancer Institute grant 1R43CA141870 (DW), National Cancer Institute grants P01 CA98912, R01 CA122602, and Department of Defense PC060866 (LWKC).

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

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Journal Title:

Molecular Cancer

Volume:

Volume 9

Publisher:

, Pages 9-9

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Abstract:

Background Myeloid 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. Results Immunohistochemical 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. Conclusions This 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.

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©2010 Zhang et al; licensee BioMed Central Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 2.0 Generic License (http://creativecommons.org/licenses/by/2.0/).

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