Abstract
Our previous work showed that Zbed3 is overexpressed in nonsmall cell lung cancer and that down‐regulation of Zbed3 inhibited β‐catenin expression and cancer cell proliferation and invasiveness. Here, we investigated Zbed3's ability to promote lung cancer cell proliferation and invasion and the involvement of the Axin/TPC/glycogen synthase kinase 3β (Gsk‐3β) complex to the response. Coimmunoprecipitation assays showed that wild‐type Zbed3 bound to Axin but a Zbed3 mutant lacking the Axin binding site did not. In A549 and H1299 lung cancer cells, Zbed3 overexpression promoted cancer cell proliferation and invasiveness, as well as Wnt signalling and expression of downstream mediators, including β‐catenin, cyclin D1 and MMP7 (P < 0.05). In contrast, the Zbed3 mutant failed to enhance β‐catenin expression (P > 0.05), and its ability to promote cancer cell proliferation and invasiveness was much less than wild‐type Zbed3 (P < 0.05). The ability of Zbed3 to increase β‐catenin levels was abolished by Axin knockdown in A549 cells (P > 0.05). Similarly, treating the cells with a GSK‐3β inhibitor abolished Zbed3's ability to increase β‐catenin levels and Wnt signalling. These results indicate that Zbed3 enhances lung cancer cell proliferation and invasiveness at least in part by inhibiting Axin/adenomatous polyposis coli/GSK‐3β‐mediated negative regulation of β‐catenin levels.
Highlights
The ability of Zbed[3] to promote Wnt signalling was abolished in TWS119‐treated cells (Figure 8B). These results indicate that Zbed3's ability to increase β‐catenin expression and Wnt signalling activity was dependent on the activity of the Axin/adenomatous polyposis coli (APC)/glycogen synthase kinase 3β (GSK‐3β) complex
Down‐regulation of Zbed[3] in lung cancer cells significantly reduced expression of β‐catenin and p120‐catenin 1, both of which are degraded through similar pathways, but the mechanism involved is not completely clear
It is known that β‐catenin degradation is mediated by the Axin/APC/GSK3β complex when Wnt signalling is not activated,[5,6] and that Zbed[3] may regulate β‐catenin by interacting with Axin and inhibiting the function of Axin/APC/GSK3β complex.[10]
Summary
Abnormal Wnt signalling contributes to the development and progression of many malignancies.[1,2,3,4] β‐catenin is a key mediator of Wnt signalling that is degraded via a complex composed of Axin, adenomatous polyposis coli (APC), and serin/threonine glycogen synthase kinase 3β (GSK‐3β) when Wnt signalling is not activated.[5,6] When activated, Wnt signalling activates Disheveled, which in turn inhibits phosphorylation of β‐catenin by the Axin/APC/GSK‐3β complex and prevents its degradation via the ubiquitin proteasome. β-catenin is accumulated in cytoplasm and translocated to the nucleus, where it binds to and activates transcription factor T-cell factor/Lymphoid, enhancer, factor, thereby regulating expression of target genes.[5,6]. We previously observed that Zbed[3] is overexpressed in nonsmall cell lung cancer (NSCLC) and acts as a positive regulator of β‐catenin to promote NSCLC malignancy.[7] abnormal Axin (Axin). We previously observed that Zbed[3] is overexpressed in nonsmall cell lung cancer (NSCLC) and acts as a positive regulator of β‐catenin to promote NSCLC malignancy.[7] abnormal Axin (Axin1) To better understand the molecular mechanism of action of Zbed[3] in NSCLC, in the present study we investigated the effects of Zbed[3] on β‐catenin expression and the proliferation and invasiveness of NSCLC cells
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