title: A proteomic study of resistance to deoxycholate-induced apoptosis.
abstract: The development of apoptosis resistance appears to be an important factor in colon carcinogenesis. To gain an understanding of the molecular pathways altered during the development of apoptosis resistance, we selected three cell lines for resistance to induction of apoptosis by deoxycholate, an important etiologic agent in colon cancer. We then evaluated gene expression levels for 825 proteins in these resistant lines, compared with a parallel control line not subject to selection. Eighty-two proteins were identified as either over-expressed or under-expressed in at least two of the resistant lines, compared with the control. Thirty-five of the 82 proteins (43%) proved to have a known role in apoptosis. Of these 35 proteins, 21 were over-expressed and 14 were under-expressed. Of those that were over-expressed 18 of 21 (86%) are anti-apoptotic in some circumstances, of those that were under-expressed 11 of 14 (79%) are pro-apoptotic in some circumstances. This finding suggests that apoptosis resistance during selection among cultured cells, and possibly in the colon during progression to cancer, may arise by constitutive over-expression of multiple anti-apoptotic proteins and under-expression of multiple pro-apoptotic proteins. The major functional groups in which altered expression levels were found are post-translational modification (19 proteins), cell structure (cytoskeleton, microtubule, actin, etc.) (17 proteins), regulatory processes (11 proteins) and DNA repair and cell cycle checkpoint mechanisms (10 proteins). Our findings, overall, bear on mechanisms by which apoptosis resistance arises during progression to colon cancer and suggest potential targets for cancer treatment. In addition, assays of normal-appearing mucosa of colon cancer patients, for over- or under-expression of genes found to be altered in our resistant cell lines, may allow identification of early biomarkers of colon cancer risk.
authors.affiliation: Department of Microbiology and Immunology, Arizona Cancer Center, Tucson, AZ 85724, USA.
authors.forename: Harris
authors.initials: H
authors.lastname: Bernstein
authors.forename: Claire M
authors.initials: CM
authors.lastname: Payne
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kunke
authors.forename: Cara L
authors.initials: CL
authors.lastname: Crowley-Weber
authors.forename: Caroline N
authors.initials: CN
authors.lastname: Waltmire
authors.forename: Katerina
authors.initials: K
authors.lastname: Dvorakova
authors.forename: Hana
authors.initials: H
authors.lastname: Holubec
authors.forename: Carol
authors.initials: C
authors.lastname: Bernstein
authors.forename: Richard R
authors.initials: RR
authors.lastname: Vaillancourt
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Raynes
authors.forename: Vincent
authors.initials: V
authors.lastname: Guerriero
authors.forename: Harinder
authors.initials: H
authors.lastname: Garewal
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001647:Bile Acids and Salts / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D003840:Deoxycholic Acid / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D040901:Proteomics; D014407:Tumor Cells, Cultured
chemical_list: D001647:Bile Acids and Salts; D003902:Detergents; D009363:Neoplasm Proteins; D003840:Deoxycholic Acid