Novel Peptide Inhibitors Of Beta-Catenin Effectively Suppress The Tumorigenesis Of Colorectal Cancer

Aberrant beta-catenin activation promotes the proliferation and survival of several types of tumor cells, including colorectal cancer (CRC) cells. Synthetic peptides are drug candidates for treating various diseases; however, peptide inhibitors of beta-catenin have been rarely reported. A series of peptide inhibitors for beta-catenin (F15A(1-9k), F15A(2-9k), and F15A(3-9k)) were designed and synthesized, and then used to treat human CRC cells (HT-29). Next, a series of in vitro assays, including cell counting, colony formation, flow cytometry, and Transwell assays, were performed to assess the biological effects of the peptides on CRC cells. Mouse xenograft models of HT-29 tumors were also used to evaluate the inhibitory effect of the peptide inhibitors on beta-catenin expression in vivo. The inhibitory effect of the peptide inhibitors on beta-catenin production was tested in a confocal laser scanning microscope study (CLSMS), and by H&E, TUNEL, and immunohistochemical (IHC) staining. The peptide inhibitors significantly reduced the viability of HT-29 cells in time- and concentration-dependent manners. Moreover, the peptide inhibitors for beta-catenin significantly inhibited CRC tumorigenesis both in vitro and in vivo. Mechanistically, the peptide inhibitors for beta-catenin inhibited the angiogenesis activity of HT-29 cells. When administered by itself, F15A(2-9k) blocked cell division, induced apoptosis, and reduced the migration and invasion capabilities of HT-29 cells, while a combination of F15A(1-9k), F15A(2-9k), and F15A(3-9k) showed even stronger inhibitory effects on HT-29 cells. In summary, the peptides designed to inhibit beta-catenin demonstrated anti-tumor activity both in vitro and in vivo, suggesting their potential as therapeutic agents for treating CRC.