Although it is known that accumulation of oncogenic β-
catenin is critical for intestinal
tumorigenesis, the underlying mechanisms have not yet been fully explored. Post-translational β-
catenin level is regulated via the
adenomatous polyposis coli (APC)-dependent as well as the APC-independent
ubiquitin-
proteasome pathway (UPP). Employing an APC-mutant mouse model (APC(Min/+)) the present study aimed to investigate the status of RXRα, an APC-independent factor involved in targeting β-
catenin to UPP for degradation, in
tumor-bearing and
tumor-free areas of intestine after exposure to energetic (56)Fe
ions. APC(Min/+) mice were exposed to energetic (56)Fe
ions (4 or 1.6 Gy) and intestinal
tumor samples and
tumor-free normal intestinal samples were collected 100-110 days after exposure. The status of TCF4, β-
catenin,
cyclin D1, and RXRα was examined using immunohistochemistry and immunoblots. We observed increased accumulation of the
transcription factor TCF4 and its co-activator β-
catenin as well as their downstream oncogenic target
protein cyclin-D1 in (56)Fe ion-induced intestinal
tumors. Further, decreased expression of RXRα in
tumors as well as in adjacent normal epithelium was indicative of perturbations in β-
catenin proteasomal-targeting machinery. This indicates that decreased UPP targeting of β-
catenin due to downregulation of RXRα can contribute to further accumulation of β-
catenin and to (56)Fe-induced
tumorigenesis.