Decreased RXRα is Associated with Increased β-Catenin/TCF4 in (56)Fe-Induced Intestinal Tumors.
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.
Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University , Washington, DC , USA.
Shubhankar
S
Suman
Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University , Washington, DC , USA.
Santosh
S
Kumar
Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University , Washington, DC , USA ; Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University , Jeddah , Saudi Arabia.
Albert J
AJ
Fornace
Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University , Washington, DC , USA.
Kamal
K
Datta
APCMin/+; heavy ion radiation; intestinal tumor; proteasome; space radiation; tumorigenesis; β-catenin