Inhibition of Tankyrases Induces Axin Stabilization and Blocks Wnt Signalling in Breast Cancer Cells

Abstract

Constitutive Wnt signalling is characterized by excessive levels of β-catenin protein and is a frequent occurrence in cancer. APC and Axin are key components of the β-catenin destruction complex that acts to promote β-catenin degradation. The levels of Axin are in turn controlled by tankyrases, members of the PARP-family of poly-ADP-ribosylation enzymes. In colorectal cancer cells, which typically harbor APC mutations, inhibition of tankyrase activity promotes Axin stabilization and attenuates Wnt signalling. Here, we examined the effect of inhibiting tankyrases in breast cancer cells with normal APC. We show that application of the small molecule tankyrase inhibitor, XAV939 or siRNA-mediated abrogation of tankyrase expression increases Axin1 and Axin2 protein levels and attenuates Wnt-induced transcriptional responses in several breast cancer lines. In MDA-MB-231 cells, inhibiton of tankyrase activity also attenuate Wnt3a induced cell migration. Moreover, in both MDA-MB-231 and colorectal cancer cells, XAV939 inhibits cell growth under conditions of serum-deprivation. However, the presence of serum prevents this growth inhibitory effect, although inhibition of Wnt-induced transcriptional and migratory responses was maintained. These results indicate that stabilization of Axin by inhibition of tankyrases alone, may not be an effective means to block tumor cell growth and that combinatorial therapeutic approaches should be considered.

Tankyrase-mediated β-catenin activity regulates vasopressin-induced AQP2 expression in kidney collecting duct mpkCCDc14 cells

“…An in vitro IC 50 test revealed that the IC 50 of XAV939 was 4 and 11 nM against activity of tankyrase-1 and tankyrase-2, respectively (15). Although XAV939 showed in vitro an IC 50 value with high selectivity, higher concentrations (5-10 M) of XAV939 were commonly chosen for cell-based experiments to examine the inhibitory effects of XAV939 on tankyrase activity and tankyrase-mediated Wnt signaling (1,8,14). Importantly, dDAVP-or forskolin-induced AQP2 upregulation was significantly attenuated by the inhibition of tankyrase with 10 M XAV939 treatment or siRNA-mediated knockdown, indicating that tankyrase and/or tankyrase-mediated signaling is importantly involved in AQP2 regulation.…”

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

“…cer, hepatocarcinoma, medulloblastoma, ovarian cancer, and breast cancer) can also exhibit loss of functional axin or other mutations that stabilize ␤-catenin expression (21)(22)(23)(24)(25)(26). These findings have prompted researchers to develop inhibitors of the WNT/ ␤-catenin signaling pathway for therapeutic use to treat cancer, although the vast majority of these are still at the preclinical testing stage (27).…”

Inhibiting Tankyrases Sensitizes KRAS-Mutant Cancer Cells to MEK Inhibitors via FGFR2 Feedback Signaling

“…However, inhibition of TNKS is not sufficient to fully suppress Wnt signaling, resulting in only partial tumor growth inhibition (15). Several reports have also shown that the antitumor effect following TNKS inhibition is more robust under serumdeprived conditions (8,15,20,21), raising the possibility that TNKS inhibition may be more effective when combined with other therapies. This idea is supported by two studies reporting that TNKS inhibition could alleviate resistance to EGFR inhibitors in non-small lung cancer cell lines and potentiates colorectal cancer cell response to PI3K/AKT pathway inhibitors (22,23).…”