ABSTRACT
Peroxisome-proliferator activated receptor-gamma (PPARgamma) has been demonstrated to exert an inhibitory effect on cell growth in most cell types studied, but its role in colon cancer is still uncertain. The molecular mechanism between the activation of PPARgamma and its consequence is unknown. In the present report, we show that the expression of PPARgamma was significantly increased in tumor tissues from human colon cancer compared with non-tumor tissues and that PPARgamma ligands, 15-Deoxy-delta(12,14)prostaglandin J2 or ciglitizone, induced apoptosis in HT-29 cells, a human colon cancer cell line. The occurrence of apoptosis induced by PPARgamma ligands was sequentially accompanied by reduced levels of NF-kappaB and Bcl-2. Over-expression of Bcl-2 significantly protected the cells from apoptosis. This study suggested that a PPARgamma-Bcl-2 feedback loop may function to control the life-death continuum in colonic cells and that a deficiency in generation of PPARgamma ligands may precede the development of human colon cancer.
Subject(s)
Apoptosis/drug effects , Colon/metabolism , Colonic Neoplasms/metabolism , NF-kappa B/metabolism , Prostaglandin D2/analogs & derivatives , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Thiazolidinediones , Transcription Factors/metabolism , Cell Division , Cell Survival/drug effects , Colonic Neoplasms/pathology , DNA-Binding Proteins/metabolism , Electrophoretic Mobility Shift Assay , HT29 Cells , Humans , Hypoglycemic Agents/pharmacology , Immunoenzyme Techniques , Immunologic Factors/pharmacology , Ligands , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , Promoter Regions, Genetic , Prostaglandin D2/pharmacology , Signal Transduction , Thiazoles/pharmacology , Transcription, GeneticABSTRACT
CONTEXT: Disturbance in apoptosis has been proposed as one of the mechanisms involved in the immune response targeting tumor outgrowth. How colorectal cancer cells escape from attack by the immune system is not yet fully understood. OBJECTIVE: To investigate apoptotic molecules associated with colorectal cancer counterattack. DESIGN AND SETTING: Tissue samples of colon from 12 patients with colorectal cancer were collected and analyzed by immunostaining. In addition to tumorous tissues, corresponding nontumorous specimens of colon were obtained as controls. MAIN OUTCOME MEASURES: We examined the expression of Bcl-2, Bcl-xl, Bax, caspase-3, and inducible nitric oxide synthase in infiltrating mononuclear cells of colorectal cancer tissues and also in colorectal cancer tissues. The TUNEL assay was used to detect in situ apoptosis. RESULTS: Apoptosis was barely detectable in specimens of colorectal cancer, which was consistent with an increase in Bcl-2 level and a decrease in caspase-3 level. In contrast, infiltrating mononuclear cells of tumorous tissues showed a marked increase in apoptosis compared with those of nontumorous tissues. The increased apoptosis might have resulted from an imbalance of antiapoptotic and proapoptotic molecules, as reflected by reduction of Bcl-2 level and elevation of Bax level. The elevated caspase-3 levels found in this study could be a downstream effector of the Bcl-2 and Bax apoptotic pathways. A significant increase in inducible nitric oxide synthase observed in the infiltrating mononuclear cells might contribute to immunosuppression seen in colorectal cancer. CONCLUSION: It is tempting to speculate that aberrant expression of apoptotic molecules and inducible nitric oxide synthase in infiltrating mononuclear cells provides the underlying mechanism through which colorectal cancer cells escape attack by the immune system and subsequently grow without control.
