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

Zhang S, Zhau HE, Osunkoya AO, Iqbal S, Yang X, Fan S, Chen Z, Wang R, Marshall FF, Chung LW, Wu D - Mol. Cancer (2010)

Bottom Line: We further found that vascular endothelial growth factor (VEGF) is a novel regulator of Mcl-1 expression 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.This study demonstrated that Mcl-1 overexpression is associated with PCa bone metastasis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. szhang5@emory.edu

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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Related in: MedlinePlus

c-MET signaling is required for VEGF165 induction of Mcl-1 in ARCaPM cells. (a) Effects of c-MET inhibition on Mcl-1 expression. ARCaPM cells were transfected with c-MET siRNA or control siRNA (30 nM) for 72 h. (b) Effects of recombinant HGF treatment (10 ng/ml) on Mcl-1 expression at RNA (0, 2, 4 and 6 h) and protein levels (72 h). (c) ARCaPM cells were transfected with c-MET siRNA or control siRNA for 48 h, serum-starved overnight, and treated with VEGF165 (10 ng/ml) for 2 h. (d) ARCaPM cells were treated with PHA-665752 (0.5 μM) or dimethyl sulfoxide (DMSO) for 2 h, before treatment with VEGF165 (10 ng/ml) or PBS for 2 h.
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Figure 4: c-MET signaling is required for VEGF165 induction of Mcl-1 in ARCaPM cells. (a) Effects of c-MET inhibition on Mcl-1 expression. ARCaPM cells were transfected with c-MET siRNA or control siRNA (30 nM) for 72 h. (b) Effects of recombinant HGF treatment (10 ng/ml) on Mcl-1 expression at RNA (0, 2, 4 and 6 h) and protein levels (72 h). (c) ARCaPM cells were transfected with c-MET siRNA or control siRNA for 48 h, serum-starved overnight, and treated with VEGF165 (10 ng/ml) for 2 h. (d) ARCaPM cells were treated with PHA-665752 (0.5 μM) or dimethyl sulfoxide (DMSO) for 2 h, before treatment with VEGF165 (10 ng/ml) or PBS for 2 h.

Mentions: A c-MET siRNA construct was transfected into ARCaPM cells, which effectively inhibited endogenous c-MET (Figure 4a). c-MET siRNA treatment reduced Mcl-1 protein expression, suggesting that c-MET is involved in maintaining basal expression of Mcl-1 in PCa cells. Interestingly, however, recombinant HGF treatment did not significantly affect Mcl-1 expression at either RNA or protein levels (Figure 4b), indicating that HGF-dependent activation of c-MET signaling is not sufficient to induce Mcl-1 expression in these cells.


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

Zhang S, Zhau HE, Osunkoya AO, Iqbal S, Yang X, Fan S, Chen Z, Wang R, Marshall FF, Chung LW, Wu D - Mol. Cancer (2010)

c-MET signaling is required for VEGF165 induction of Mcl-1 in ARCaPM cells. (a) Effects of c-MET inhibition on Mcl-1 expression. ARCaPM cells were transfected with c-MET siRNA or control siRNA (30 nM) for 72 h. (b) Effects of recombinant HGF treatment (10 ng/ml) on Mcl-1 expression at RNA (0, 2, 4 and 6 h) and protein levels (72 h). (c) ARCaPM cells were transfected with c-MET siRNA or control siRNA for 48 h, serum-starved overnight, and treated with VEGF165 (10 ng/ml) for 2 h. (d) ARCaPM cells were treated with PHA-665752 (0.5 μM) or dimethyl sulfoxide (DMSO) for 2 h, before treatment with VEGF165 (10 ng/ml) or PBS for 2 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2820018&req=5

Figure 4: c-MET signaling is required for VEGF165 induction of Mcl-1 in ARCaPM cells. (a) Effects of c-MET inhibition on Mcl-1 expression. ARCaPM cells were transfected with c-MET siRNA or control siRNA (30 nM) for 72 h. (b) Effects of recombinant HGF treatment (10 ng/ml) on Mcl-1 expression at RNA (0, 2, 4 and 6 h) and protein levels (72 h). (c) ARCaPM cells were transfected with c-MET siRNA or control siRNA for 48 h, serum-starved overnight, and treated with VEGF165 (10 ng/ml) for 2 h. (d) ARCaPM cells were treated with PHA-665752 (0.5 μM) or dimethyl sulfoxide (DMSO) for 2 h, before treatment with VEGF165 (10 ng/ml) or PBS for 2 h.
Mentions: A c-MET siRNA construct was transfected into ARCaPM cells, which effectively inhibited endogenous c-MET (Figure 4a). c-MET siRNA treatment reduced Mcl-1 protein expression, suggesting that c-MET is involved in maintaining basal expression of Mcl-1 in PCa cells. Interestingly, however, recombinant HGF treatment did not significantly affect Mcl-1 expression at either RNA or protein levels (Figure 4b), indicating that HGF-dependent activation of c-MET signaling is not sufficient to induce Mcl-1 expression in these cells.

Bottom Line: We further found that vascular endothelial growth factor (VEGF) is a novel regulator of Mcl-1 expression 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.This study demonstrated that Mcl-1 overexpression is associated with PCa bone metastasis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. szhang5@emory.edu

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.

Show MeSH
Related in: MedlinePlus