Abstract
Semaphorins are secreted proteins that have a role in chemotaxis and are implicated in cancer. Plexins are membrane-bound receptors for semaphorins. We have found a high frequency of mutations in the plexinB1 gene and overexpression of the protein in prostate tumours (Wong et al., 2007; PNAS 104: 19040-5) indicating a role for plexinB1 in the pathogenesis of prostate cancer. The mutations of plexinB1 found in prostate tumours are functionally significant, increasing cell motility, invasive capacity, adhesion and inhibiting cell collapse. The mutations affect signalling pathways downstream of plexinB1, inhibiting Rac, Rnd, and R-Ras binding to plexinB1 and R-RasGAP activity. The mutations have the net effect of increasing cell motility by the loss of inhibitory pathways.
We have now found that knockdown of endogenous plexinB1 in the prostate cancer cell line LNCaP inhibits anchorage-independent growth, while stimulation with semaphorin4D, the ligand for plexinB1, increases the migration and invasive capacity of LNCaP cells. These effects are reversed by expression of shRNA to plexinB1. Stimulation with semaphorin4D also results in ErbB2 and Akt activation. The opposite effects occur in the prostate cancer cell line PC3 in response to semaphorin4D. The opposite response of LNCaP and PC3 may be due to high levels of ErbB2 or c-Met expressed by the two cell lines respectively. These findings provide evidence for a subset of prostate tumours in which plexinB1 acts as a tumour-enhancing gene by activating ErbB2 and in which mutation of plexinB1 results in loss of cancer-inhibitory pathways.
Citation Format: Magali Williamson, John Masters. Mutation of PlexinB1 in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B55.
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