Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells.
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.
Zhang
Shumin
S
Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. szhang5@emory.edu
Zhau
Haiyen E
HE
Osunkoya
Adeboye O
AO
Iqbal
Shareen
S
Yang
Xiaojian
X
Fan
Songqing
S
Chen
Zhengjia
Z
Wang
Ruoxiang
R
Marshall
Fray F
FF
Chung
Leland W K
LW
Wu
Daqing
D
D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D039942:Neuropilin-1 / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D017978:Receptors, Growth Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040262:Receptors, Vascular Endothelial Growth Factor; D019061:src-Family Kinases