Abstract A10: Redox regulation of the Wnt/β-catenin pathway in colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is the third most newly diagnosed cancer, and the third most frequent cause of cancer related death in the United States. Thus, there is an urgent unmet need for the development of new therapies for the treatment of CRC. Loss of function mutations in adenomatous polyposis coli (APC), a critical member of the β-catenin destruction complex, lead to elevated protein levels of β-Catenin, and are found in 85% of CRCs, where they are associated with decreased CRC patient survival. Increased levels of β-catenin protein augment the nuclear accumulation of β-catenin where it interacts with transcription factors to induce transcription of target genes promoting cell proliferation, survival, and migration. Currently, there is still no effective therapy targeting aberrant β-catenin transcriptional activity. Here we report on the redox dependency of the Wnt/β-catenin signaling pathway, identified through a forward genetic screen in Drosophila, and identify TxnR1 as a potential target for the inhibition of aberrant β-catenin transcriptional activity through in vivo studies with the APCmin/+ mouse model. Drosophila harboring a mutation in the thioredoxin reductase (txnr1) gene that have a partial lethality phenotype were used in an enhancer/suppressor forward genetic screen. Increased lethality was observed when the txnr1 mutation (Txnr1481) was combined with heterozygous mutations and deletions in dwnt2, while dwnt2 deletion and mutations alone had no effect (on lethality). In addition, β-Catenin mediated transcription, as measured by TOP Flash luciferase assay, was diminished when TxnR1 was silenced by siRNA. To test the translational value of these findings, APCmin/+ mice were treated with PX-12, a human TxnR1 inhibitor, daily by gavage from day 40 to time of death. We observed a dose dependent reduction in the number and size of intestinal polyps by PX-12 treatment, and an increased survival in treated mice. Also, human colorectal cancer cell lines treated with PX-12 displayed attenuated phosphorylation of β-catenin serine residues 552 and 675. These results suggest a conserved mechanism for the redox regulation of the Wnt/β-catenin pathway involving TxnR1; furthermore, inhibition of TxnR1 can inhibit intestinal neoplasia development in an experimental model of CRC. Citation Format: Alex Campos, Brian James, Petrus De Jong, Garth Powis. Redox regulation of the Wnt/β-catenin pathway in colorectal cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A10.