Tumor and Stem Cell Biology a-Catulin Drives Metastasis by Activating ILK and Driving an a v b 3 Integrin Signaling Axis

a-Catulin is an oncoprotein that helps sustain proliferation by preventing cellular senescence. Here, we report that a-catulin also drives malignant invasion and metastasis. a-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. a-Catulin interacted with integrin-linked kinase (ILK), a serine/threonine protein kinase implicated in cancer cell proliferation, antiapoptosis, invasion, and angiogenesis. Attenuation of ILK ora-catulin reciprocally blocked cell migration and invasion induced by the other protein. Mechanistic investigations revealed that a-catulin activated Akt-NF-kB signaling downstream of ILK, which in turn led to increased expression of fibronectin and integrin avb3. Pharmacologic or antibodymediated blockade of NF-kB or avb3 was sufficient to inhibit a-catulin–induced cell migration and invasion. Clinically, high levels of expression ofa-catulin and ILKwere associatedwith poor overall survival in patientswith NSCLC. Taken together, our study shows that a-catulin plays a critical role in cancer metastasis by activating the ILK-mediated Akt-NF-kB-avb3 signaling axis. Cancer Res; 73(1); 428–38. 2012 AACR.