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

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.

Pathways of chemotherapy resistance in castration-resistant prostate cancer

“…This suggests that the apoptotic action of taxane chemotherapy may rely, in part, on an interaction with Bcl2 rather than being mediated solely by microtubule stabilisation. Yoshino et al (2006) further supported this theory with the finding that higher Bcl2 expression in prostate cancer tissue at et al , Zhang et al 2010.…”

A Novel Inhibitor of c-Met and VEGF Receptor Tyrosine Kinases with a Broad Spectrum of In Vivo Antitumor Activities

“…In agreement with previous studies on this subject, hypoxia indeed upregulated c-Met expression and promoted HGF-induced cell invasion. Moreover, we found that hypoxia elevated c-Met phosphorylation levels even in the absence of HGF stimuli, although this may be partly explained through the recent findings that hypoxia promotes interaction between c-Met and neuropilin-1, a coreceptor for VEGF-A, which in turn facilitates VEGFinduced c-Met activation (43). These results indicate a key role of c-Met activation in response to the hypoxic stress of cancer cells.…”

Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: ‘Game Over’?

“…While MET and HGF are found in low levels in normal adult tissues, ectopic activation of MET has been observed in primary and metastatic prostate carcinomas [20,21], with higher levels of expression in bone metastases than in primary tumors and lymph node metastases [22,23]. Moreover, in preclinical animal models, overexpression of MET and/or HGF has been shown to stimulate tumorigenesis and metastasis [24], indicating a potential role of the MET/ HGF signaling in the pathogenesis of human cancer [25].…”

“…Of interest, dysregulation of the MET/VEGFR signaling is found in a broad spectrum of human malignancies, including prostate cancer [33,34] and high levels of either HGF or VEGF in plasma or urine correlate with poor prognosis, shorter overall survival, and tumor angiogenesis and proliferation [35][36][37]. In particular, Zhang and colleagues demonstrated that overexpression of myeloid cell leukemia-1 (Mcl-1), a member of the Bcl-2 family which inhibits cell apoptosis, was associated with clinical progression of some solid tumors including prostate cancer and that VEGF regulates Mcl-1 expression in a METdependent manner via the co-receptor neuropilin-1 [22]. Preclinical studies in mice have also found that cancers have the ability to develop adaptive or evasive resistance to VEGF pathway-targeted therapies [38].…”