A comprehensive strategy to combat colon cancer targeting the adenomatous polyposis coli tumor suppressor gene.
Somatic cells in the majority of colorectal polyps and cancers contain mutations/deletions in the adenomatous polyposis coli (APC) tumor suppressor gene. APC is involved in normal intestinal development and acts to influence a variety of cellular processes. Loss of APC function leads to intestinal neoplasia in both mice and humans. APC influences expression of specific genes, including the c-Myc oncogene, which functions as a transcriptional activator. Loss of APC function leads to alterations in c-Myc-regulated genes including ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis. A single nucleotide polymorphism (SNP) in the ODC promoter affecting c-Myc-dependent expression has been associated with risk of colorectal and other cancers. Pharmaceuticals that target structural features of the c-Myc promoter, and suppress expression of c-Myc and other genes regulated by similar promoter elements, are being developed as potential colorectal cancer chemotherapies. Difluoromethylornithine (DFMO), a selective inhibitor of ODC, is under clinical evaluation as a colorectal cancer chemopreventive agent. APC and APC-dependent genes, such as c-Myc and ODC, may be useful as genetic markers of risk and as targets for chemoprevention and therapy for colorectal cancer.
Gerner
Eugene W
EW
The University of Arizona, Arizona Cancer Center, Tucson, AZ 85724, USA. egerner@azcc.arizona.edu
Ignatenko
Natalia A
NA
Lance
Peter
P
Hurley
Laurence H
LH
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000518:Eflornithine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; D016271:Proto-Oncogene Proteins c-myc; D001241:Aspirin; D000518:Eflornithine