Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform.
Bottom Line: Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading.It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival.In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading.
Affiliation: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy.Show MeSH
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Mentions: Despite this apparent lack of activity, we found that Uncl-Sema3E is fully capable of binding the receptor PlexinD1 in analogy to p61-Sema3E isoform (Fig 2A). Moreover, we found that Uncl-Sema3E selectively competes with p61 for binding the receptor in the same nanomolar concentration range (Fig 2B). We then asked whether Uncl-Sema3E may potentially act as a dominant-negative molecule by interfering with p61 signalling. Indeed, ErbB2 transactivation elicited by p61 in A549 cells was strikingly reduced in the presence of Uncl-Sema3E (Fig 2C). Furthermore, data shown above in Fig 1C revealed that the basal level of ErbB2 tyrosine phosphorylation decreased in cells treated with Uncl-Sema3E, consistent with its functional competition with endogenous p61.
Affiliation: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy.