α-Catulin Drives Metastasis by Activating ILK and Driving an αvβ3 Integrin Signaling Axis

alpha-Catulin is an oncoprotein that helps sustain proliferation by preventing cellular senescence. Here, we report that alpha-catulin also drives malignant invasion and metastasis. alpha-Catulin was upregulated in highly invasive non-small cell lung cancer (NSCLC) cell lines, where its ectopic expression or short-hairpin RNA-mediated attenuation enhanced or limited invasion or metastasis, respectively. alpha-Catulin interacted with integrin-linked kinase (ILK), a serine/threonine protein kinase implicated in cancer cell proliferation, antiapoptosis, invasion, and angiogenesis. Attenuation of ILK or alpha-catulin reciprocally blocked cell migration and invasion induced by the other protein. Mechanistic investigations revealed that alpha-catulin activated Akt-NF-kappa B signaling downstream of ILK, which in turn led to increased expression of fibronectin and integrin alpha v beta 3. Pharmacologic or antibody-mediated blockade of NF-kappa B or alpha v beta 3 was sufficient to inhibit alpha-catulin-induced cell migration and invasion. Clinically, high levels of expression of alpha-catulin and ILK were associated with poor overall survival in patients with NSCLC. Taken together, our study shows that alpha-catulin plays a critical role in cancer metastasis by activating the ILK-mediated Akt-NF-kappa B-alpha v beta 3 signaling axis. Cancer Res; 73(1); 428-38. (C)2012 AACR.