α-Catulin knockdown induces senescence in cancer cells

Abstract

Cellular senescence functions as a tumor suppressor that protects against cancer progression. a-Catulin, an a-catenin-related protein, is reported to have tumorigenic potential because it regulates the nuclear factor-jB (NF-jB) pathway, but little is known about its clinical relevance and the mechanism through which it regulates cancer progression. Here, we found that a-catulin mRNA levels were significantly upregulated in cancer cell lines and clinical oral squamous cell carcinomas, which positively correlated with tumor size (P ¼ 0.001) and American Joint Committee on Cancer (AJCC) stage (P ¼ 0.004). a-Catulin knockdown in the OC2 and A549 cancer cell lines dramatically decreased cell proliferation and contributed to cellular senescence, and inhibited OC2 xenograft growth. Mechanistic dissection showed that a-catulin depletion strongly induced the DNA-damage response (DDR) in both cell lines, via a p53/p21-dependent pathway in A549 cells, but a p53/p21-independent pathway in OC2 cells carrying mutant p53. Global gene expression analysis revealed that a-catulin knockdown altered cell-cycle regulation and DDR pathways at the presenescent stage as well as significantly downregulate several crucial genes related to mitotic chromosome condensation, DDR and DNA repair systems, which suggests that its depletion-induced cellular senescence might be caused by chromosome condensation failures, severe DNA damage and impaired DNA repair ability. Our study provides evidence that a-catulin promotes tumor growth by preventing cellular senescence and suggests that downregulating a-catulin may be a promising therapeutic approach for cancer treatment.

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

“…We have found that silencing a-catulin in cancer cells decreased cell proliferation in vitro and in vivo (10). In this study, although a-catulin overexpression did not alter the cell proliferation rate, it promoted tumor growth in vivo (Supplementary Figs.…”

“…Inhibiting a-catulin, ILK, NF-kB, or integrin a V b 3 prevented cancer cell migration and invasion. In addition, a-catulin is known to have oncogenic potential through its interaction with IKK-b and induction of NF-kB activity (9) and by preventing cellular senescence (10). Moreover, inhibitors of ILK (27), NF-kB (45), and integrin (46) have been used in animal model studies and clinical trials.…”

“…a-Catulin may also play a role in cancer because it can directly interact with inhibitor of IkB kinase (IKK)-b and activate NFkB signaling, which promotes cancer cell migration and resistance to apoptosis (9). We recently reported that a-catulin is upregulated in both cancer cell lines and oral squamous cell carcinomas, and knocking down a-catulin induces cellular senescence (10).…”

α-Catulin Marks the Invasion Front of Squamous Cell Carcinoma and Is Important for Tumor Cell Metastasis

“…To address previous findings (26) that α-catulin-deficient cells are more apoptotic, we analyzed control and α-catulin-deficient human SCC cells for AnnexinV activity under normal culture conditions and after the induction of apoptosis (Supplementary Fig. S3B).…”

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

“…Notably, the majority of colon cancers have mutations in APC leading to protein truncation (Fodde et al, 2001b;Kinzler and Vogelstein, 1996;Smith et al, 1993), and deletion of APC in crypt stem cells in mice leads to transformation within days (Barker et al, 2009). α-Catulin (also known as CTNNAL1), a vinculin-related protein with homology to α-catenin, has also been shown to increase γH2AX levels when knocked down and may regulate cell fate (Fan et al, 2011). Taken together, these studies suggest the WNT pathway may be an important regulator of how the cell responds to DNA damage, and the mechanisms that regulate catenin activity in the cytoplasm may be conserved in the nucleus.…”