title: Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer.
abstract: Mutations in the adenomatous polyposis coli (APC) gene are common in colorectal cancer (CRC), and more than 90% of those mutations generate stable truncated gene products. We describe a chemical screen using normal human colonic epithelial cells (HCECs) and a series of oncogenically progressed HCECs containing a truncated APC protein. With this screen, we identified a small molecule, TASIN-1 (truncated APC selective inhibitor-1), that specifically kills cells with APC truncations but spares normal and cancer cells with wild-type APC. TASIN-1 exerts its cytotoxic effects through inhibition of cholesterol biosynthesis. In vivo administration of TASIN-1 inhibits tumor growth of CRC cells with truncated APC but not APC wild-type CRC cells in xenograft models and in a genetically engineered CRC mouse model with minimal toxicity. TASIN-1 represents a potential therapeutic strategy for prevention and intervention in CRC with mutant APC.
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Lu
authors: L
authors: Zhang
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Panayotis C
authors: PC
authors: Theodoropoulos
authors: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Ugur
authors: U
authors: Eskiocak
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Wentian
authors: W
authors: Wang
authors: Department of Molecular Medicine, Inha University College of Medicine, 100 Inha-ro, Nam-gu, Incheon 22212, Korea.
authors: Young-Ah
authors: YA
authors: Moon
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Bruce
authors: B
authors: Posner
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Noelle S
authors: NS
authors: Williams
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Woodring E
authors: WE
authors: Wright
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Sang Bum
authors: SB
authors: Kim
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Deepak
authors: D
authors: Nijhawan
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Jef K
authors: JK
authors: De Brabander
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. jerry.shay@utsouthwestern.edu.
authors: Jerry W
authors: JW
authors: Shay
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D002784:Cholesterol / Q000737:chemistry; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D010880:Piperidines; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D013449:Sulfonamides; C000614726:TASIN-1 compound; D002784:Cholesterol