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Carcinogenesis Advance Access published online on January 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgh072
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CANCER BIOLOGY

A proteomic study of resistance to deoxycholate-induced apoptosis

Harris Bernstein 1, Claire M. Payne 1, Kathleen Kunke 2, Cara L. Crowley-Weber 2, Caroline N. Waltmire 2, Katerina Dvorakova 2, Hana Holubec 2, Carol Bernstein 2*, Richard R. Vaillancourt 3, Deborah A. Raynes 4, Vincent Guerriero 5, and Harinder Garewal 6

1 Department of Microbiology and Immunology, University of Arizona, Tucson AZ 85724; Arizona Cancer Center, University of Arizona, Tucson AZ 85724
2 Department of Microbiology and Immunology, University of Arizona, Tucson AZ 85724
3 Department of Pharmacology & Toxicology and the Center for Toxicology, University of Arizona, Tucson AZ 85724
4 Department of Animal Science, University of Arizona, Tucson, AZ 85721
5 Department of Animal Science, University of Arizona, Tucson, AZ 85721; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721.
6 Department of Internal Medicine, College of Medicine, University of Arizona, Tucson AZ 85724; Tucson Veterans Affairs Medical Center, Section of Hematology/Oncology, Tucson, AZ 85723,

* Corresponding author. E-mail: bernstein3{at}earthlink.net.

Received 18 August 2003 ; revised 16 December 2003 ; accepted 19 December 2003

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 to 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 to 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 18/21 (86%) are anti-apoptotic in some circumstances, of those that were under-expressed 11/14 (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.

apoptosis, colon cancer, signal transduction, proteomic, bile acids
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