Limits...
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.

Show MeSH

Related in: MedlinePlus

Expression of NRP1 and p-c-MET is associated with bone metastatic status of human PCa specimens and the ARCaPM model. IHC analyses of NRP1 expression in human normal/benign, cancerous and metastatic prostatic tissue specimens (a) and primary and bone metastatic tissue specimens from ARCaPM model (b), and of p-c-MET expression in human PCa progression (c) and ARCaPM xenografts (d). Arrows indicate positively-stained cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2820018&req=5

Figure 8: Expression of NRP1 and p-c-MET is associated with bone metastatic status of human PCa specimens and the ARCaPM model. IHC analyses of NRP1 expression in human normal/benign, cancerous and metastatic prostatic tissue specimens (a) and primary and bone metastatic tissue specimens from ARCaPM model (b), and of p-c-MET expression in human PCa progression (c) and ARCaPM xenografts (d). Arrows indicate positively-stained cells.

Mentions: To validate the clinical significance of NRP1-c-MET signaling in PCa progression, and avoid the potential bias from using human PCa cell lines, IHC analyses were performed to determine the expression of NRP1 and p-c-MET in human PCa tissue specimens. Prostatic tissue specimens of normal/benign glands, primary and bone metastatic tumors were analyzed. NRP1 expression was increased from normal/benign glands (0/5) or well-differentiated cancer (1/5) to poorly-differentiated cancers (5/5) and bone metastatic tissues (5/5) (Figure 8a). NRP1 staining was also determined in tumor specimens from the ARCaPM xenograft model in which ARCaPM cells were inoculated into athymic mice orthotopically, resulting in skeletal metastases with a short latency [21]. Consistently, NRP1 expression was significantly greater in bone metastatic tumors than in primary tumors (Figure 8b).


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)

Expression of NRP1 and p-c-MET is associated with bone metastatic status of human PCa specimens and the ARCaPM model. IHC analyses of NRP1 expression in human normal/benign, cancerous and metastatic prostatic tissue specimens (a) and primary and bone metastatic tissue specimens from ARCaPM model (b), and of p-c-MET expression in human PCa progression (c) and ARCaPM xenografts (d). Arrows indicate positively-stained cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Expression of NRP1 and p-c-MET is associated with bone metastatic status of human PCa specimens and the ARCaPM model. IHC analyses of NRP1 expression in human normal/benign, cancerous and metastatic prostatic tissue specimens (a) and primary and bone metastatic tissue specimens from ARCaPM model (b), and of p-c-MET expression in human PCa progression (c) and ARCaPM xenografts (d). Arrows indicate positively-stained cells.
Mentions: To validate the clinical significance of NRP1-c-MET signaling in PCa progression, and avoid the potential bias from using human PCa cell lines, IHC analyses were performed to determine the expression of NRP1 and p-c-MET in human PCa tissue specimens. Prostatic tissue specimens of normal/benign glands, primary and bone metastatic tumors were analyzed. NRP1 expression was increased from normal/benign glands (0/5) or well-differentiated cancer (1/5) to poorly-differentiated cancers (5/5) and bone metastatic tissues (5/5) (Figure 8a). NRP1 staining was also determined in tumor specimens from the ARCaPM xenograft model in which ARCaPM cells were inoculated into athymic mice orthotopically, resulting in skeletal metastases with a short latency [21]. Consistently, NRP1 expression was significantly greater in bone metastatic tumors than in primary tumors (Figure 8b).

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