Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor-Induced Formation of Degradasomes and β-Catenin Degradation

Abstract
Recent studies have revealed that inhibiting tankyrase enzymes (TNKS1 and TNKS2) triggers the formation of highly dynamic assemblies of β-catenin destruction complex components, known as degradasomes. These structures enhance β-catenin degradation and reduce Wnt signaling activity in colorectal cancer cells. The inhibition of TNKS leads to the stabilization of AXIN1 and AXIN2/Conductin, which are crucial for maintaining the stability and function of endogenous destruction complexes. This stabilization occurs because TNKS inhibition prevents the proteasomal degradation of AXIN.

Given that the specific roles of AXIN1 and AXIN2 as scaffolding proteins in the Wnt signaling pathway are not fully understood, we aimed to investigate their relative contributions to degradasome formation. We treated SW480 colorectal cancer cells with the tankyrase inhibitor G007-LK and found that AXIN1 is not necessary for degradasome formation. However, in cells depleted of AXIN2, both degradasome formation and β-catenin degradation were significantly impaired. These results provide new insights into the distinct functional roles of G007-LK AXIN1 and AXIN2 within the β-catenin destruction complex.