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.