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

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.