Neuropilin-1 suppresses tumorigenic properties in a human pancreatic adenocarcinoma cell line lacking neuropilin-1 coreceptors.
Neuropilin-1 (NRP-1) was first described as a coreceptor implicated in neuronal guidance that bound members of the semaphorin/collapsin family. NRP-1 is also expressed in endothelial cells and is believed to promote angiogenesis by acting as a coreceptor with vascular endothelial growth factor (VEGF) receptor 2. Recent studies suggest that NRP-1 can function through both a VEGF-dependent and VEGF-independent fashion. Expression of NRP-1 has been shown in many human tumors, including pancreatic adenocarcinomas. The exact role of NRP-1 in tumor cells is unknown, particularly in cells that lack the NRP-1 coreceptors VEGF receptor 2 and Plexin-A1. To discern the regulatory role(s) of NRP-1 in pancreatic adenocarcinoma that lack these coreceptors, we overexpressed both full-length NRP-1 and a deletion form of NRP-1 that does not interact with semaphorin or VEGF. Overexpression of either isoform reduced several key tumorigenic properties, including anchorage-independent cell growth and migration in vitro, and resulted in reduced tumor incidence and tumor volume in vivo. Conversely, reduction of NRP-1 expression by small interfering RNA targeting led to enhanced tumor growth. Thus, NRP-1 may play distinct growth regulatory roles in different tumor types, and altering NRP-1 expression or function may be a means of influencing the growth of pancreatic cancers.
Gray
Michael J
MJ
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 21201, USA.
Wey
Jane S
JS
Belcheva
Anna
A
McCarty
Marya F
MF
Trevino
Jose G
JG
Evans
Douglas B
DB
Ellis
Lee M
LM
Gallick
Gary E
GE
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency*; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency*; D040121:Semaphorin-3A / Q000096:biosynthesis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000172:deficiency*
D009419:Nerve Tissue Proteins; C492116:PLXNA1 protein, human; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases