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Reduced Rap1 Signaling Is Associated with Prostate Cancer Progression, Migration, Invasion, and Metastasis

Rap1 is a small G‐protein regulator of E‐cadherin cell‐cell junctions and integrin‐mediated cell‐matrix adhesions. Our expression profiling of clinical prostate cancer tissue samples showed significantly decreased RAP1A mRNA levels in tumor compared to normal tissue samples, while a negative regulator of RAP1, RAP1GAP, was significantly increased. Furthermore, these changes in RAP1A and RAP1GAP expression are significantly correlated with Gleason tumor grade, suggesting that reduced RAP1 signals play a role in metastatic progression. We have analyzed RAP1GAP protein expression by immunohistochemistry using a tissue microarray with 139 cores from 79 prostate cancer patients, and observed that RAP1GAP staining intensity was significantly correlated with tumor grade (p < 0.001). We also show that constitutively active Rap1 signaling slows prostate cancer cell migration and invasion in vitro, while inhibition of Rap1 signaling accelerates cell migration and matrigel invasion. The PTEN‐PI3K pathway interacts with RAP1 signaling, but the mechanism is not well understood. Here we present data showing that the PTEN‐PI3K pathway is an important regulator of RAP1A and RAP1B gene expression.