Cross-talk between vascular endothelial growth factor and semaphorin-3A pathway in the regulation of normal and malignant mesothelial cell proliferation.
Vascular endothelial growth factor (VEGF) and semaphorin-3A (Sema-3A) play important roles in the transduction of promitotic and antimitotic signals, respectively. Here, we report that these conflicting signals are integrated via negative feedback between VEGF and Sema-3A pathways in several primary normal, but not malignant, mesothelial cells. Unlike malignant mesothelial (MM) cells, in which VEGF induces cell proliferation, normal mesothelial (NM) cell growth was repressed by VEGF. Although both cell-types expressed an overlapping set of VEGF tyrosine-kinase receptors, only in NM cells VEGF exposure entails a p38 mitogen-activated protein kinase (MAPK)-dependent increased of Sema-3A production. Inhibition of p38 MAPK (by SB202190 and SB203580) or a dominant-negative mutant of Sema-3A receptor plexin-A1 reversed the inhibitory effects of VEGF in NM cells, increasing cyclin D1 synthesis and cell growth. Conversely, sustained activation of p38 MAPK by the p38 MAPK-activating kinases MKK3 and MKK6 or transfection with Sema-3A inhibited VEGF-induced cyclin D1 up-regulation and MM cell proliferation. Therefore, these results delineate a new role of Sema-3A in VEGF function mediated by p38 MAPK and suggest that the abrogation of regulated Sema-3A expression is responsible for VEGF-driven growth of tumor cells.
Catalano
Alfonso
A
Department of Molecular Pathology and Innovative Therapies, Laboratory of Experimental Pathology, Polytechnic University of Marche, Ancona, Italy. catgfp@yahoo.it
Caprari
Paola
P
Rodilossi
Sabrina
S
Betta
Piergiacomo
P
Castellucci
Mario
M
Casazza
Andrea
A
Tamagnone
Luca
L
Procopio
Antonio
A
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D025461:Feedback, Physiological; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases