RCP induces Slug expression and cancer cell invasion by stabilizing β1 integrin

Rab coupling protein (RCP)-induced tumor cell migration has been implicated in tumor pathophysiology and patient outcomes. In the present study, we demonstrate that RCP stabilizes beta 1 integrin leading to increased beta 1 integrin levels and activation of a signaling cascade culminating in Slug induction, epithelial-to-mesenchymal transition and increased invasion. Ectopic expression of RCP induced Slug expression. Silencing beta 1 integrin efficiently inhibited RCP-induced Slug expression and subsequent cancer cell invasion. Conversely, ectopic expression of beta 1 integrin was sufficient to induce Slug expression. Pharmacological inhibition of integrin linked kinase ( ILK), EGFR and NF-kappa B, as well as transfection of a dominant-negative mutant of Ras (RasN17), significantly inhibited RCP-induced Slug expression and cancer cell invasion. Strikingly, ectopic expression of RCP was sufficient to enhance metastasis of ovarian cancer cells to the lung. Collectively, we demonstrate a mechanism by which RCP promotes cancer cell aggressiveness through sequential beta 1 integrin stabilization, activation of an ILK/EGFR/Ras/NF-kappa B signaling cascade and subsequent Slug expression.