8727

CTNNAL1

catenin (cadherin-associated protein), alpha-like 1;CTNNAL1;catenin (cadherin-associated protein), alpha-like 1

alpha-catenin-related protein|alpha-catulin|alpha2-catulin|catenin alpha-like protein 1

9q31.2

protein-coding

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-kappaB signaling downstream of ILK, which in turn led to increased expression of fibronectin and integrin alphavbeta3. Pharmacologic or antibody-mediated blockade of NF-kappaB or alphavbeta3 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-kappaB-alphavbeta3 signaling axis.

Squamous cell carcinomas (SCC) comprise the most common types of human epithelial cancers. One subtype, head and neck squamous cell carcinoma (HNSCC), is a particularly aggressive cancer with poor prognosis due to late diagnosis and lymph node metastasis. Of all the processes involved in carcinogenesis, local invasion and distant metastasis are clinically the most relevant, but are the least well understood on a molecular level. Here, we find that in vivo, the alpha-catenin homologue-alpha-catulin, a protein originally reported to interact with Lbc Rho guanine nucleotide exchange factor, is highly expressed at the tumor invasion front and in the metastatic streams of cells in both malignant hHNSCCs and a mouse model of oral SCC. Knockdown of alpha-catulin in hHNSCC cell lines dramatically decrease the migratory and invasive potential of those cells in vitro and metastatic potential in xenotransplants in vivo. Analysis of tumors deficient in alpha-catulin showed that the tumor cells are unable to invade the surrounding stroma. Accordingly, transcriptional profiling of those tumors revealed that alpha-catulin ablation is accompanied by changes in genes involved in cell migration and invasion. Interestingly enough, in vitro experiments show that an upregulation of alpha-catulin expression correlates with the transition of tumor cells from an epithelial to a mesenchymal morphology, as well as an upregulation of epithelial-to-mesenchymal transition (EMT) markers vimentin and snail. Overall, these results strongly indicate that alpha-catulin contributes to the invasive behavior of metastatic cells and may be used as a prognostic marker and future therapeutic target for patients with cancer.