Identification of Small Molecule Inhibitors Targeting Truncated Adenomatous Polyposis Coli (APC) as a Novel Therapeutic Strategy in Colorectal Cancer

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2014-07-18

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Zhang, Lu

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Abstract

Adenomatous polyposis coli (APC) is a tumor suppressor gene that is mutated in the vast majority of colorectal tumors. Inactivation of this gene is a key and early event in colorectal tumorigenesis. APC primarily acts as a negative regulator of Wnt pathway by aiding in degradation of β-catenin. Further studies have suggested that APC plays important roles in several other cellular processes, including cell adhesion and migration, organization of actin and microtubule networks, spindle formation and chromosome segregation. Mutations in APC gene generate truncated gene products, leading to deregulation of these processes. Accumulating evidence suggest that these C terminally truncated APC may have gain of function properties beyond their loss of tumor suppressive function. Both the gain and loss of function of APC truncations contribute to CRC initiation and progression. Utilizing a series of isogenic immortalized human colonic epithelial cells (HCECs), we have screened a 200K compound library for small molecules that exhibited selective cytotoxicity towards HCECs expressing truncated APC. We identified a compound, TASIN-1(Truncated APC Selective Inhibitor-1), which showed selective cytotoxicity towards HCECs and colorectal cancer (CRC) cells with APC truncations. TASIN-1 induces apoptotic cell death in APC truncated cells and its effect is independent of canonical Wnt pathway activity. Short hairpin RNA (shRNA) mediated knockdown of truncated APC confers resistance to TASIN-1. Additionally, TASIN-1 can interact with in vitro translated APC fragments, implicating truncated APC in the mechanism of action of TASIN-1. TASIN-1 inhibits tumor growth in both xenograft and genetic CRC mouse models. TASIN-1 may represent a novel therapeutic strategy for colon cancer prevention and intervention.

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