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

• Published in: Molecular cancer Vol. 9; no. 1; p. 9
• Main Authors: Zhang, Shumin, Zhau, Haiyen E, Osunkoya, Adeboye O, Iqbal, Shareen, Yang, Xiaojian, Fan, Songqing, Chen, Zhengjia, Wang, Ruoxiang, Marshall, Fray F, Chung, Leland W K, Wu, Daqing
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 19.01.2010; BioMed Central; BMC
• Subjects: Apoptosis; Bone Neoplasms - genetics; Bone Neoplasms - secondary; Care and treatment; Cell Survival - drug effects; Disease Progression; Enzyme Activation - drug effects; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Humans; Kinases; Male; Medical research; Models, Biological; Myeloid Cell Leukemia Sequence 1 Protein; Neuropilin-1 - metabolism; Physiological aspects; Prostate cancer; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Protein Binding - drug effects; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-met - metabolism; Receptors, Growth Factor - metabolism; Receptors, Vascular Endothelial Growth Factor - metabolism; Risk factors; Signal Transduction - drug effects; src-Family Kinases - metabolism; STAT3 Transcription Factor - metabolism; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; United States; China; Atlanta Georgia
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-9-9

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. 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. 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.