No abstract

The nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARc) has been identified as an important therapeutic target in murine models of colorectal cancer (CRC). To examine whether PPARc inhibition has therapeutic effects in late-stage CRC, the effects of PPARc inhibitors on CRC cell survival were examined in CRC cell lines and a murine CRC model. Low doses (0.1-1 lM) of PPARc inhibitors (T0070907, GW9662 and BADGE) did not affect cell survival, while higher doses (10-100 lM) of all 3 PPARc inhibitors caused caspase-dependent apoptosis in HT-29, Caco-2 and LoVo CRC cell lines. Apoptosis was preceded by altered cell morphology, and this alteration was not prevented by caspase inhibition. PPARc inhibitors also caused dual G and M cell cycle arrest, which was not required for apoptosis or for morphologic alterations. Furthermore, PPARc inhibitors triggered loss of the microtubule network. Notably, unlike other standard antimicrotubule agents, PPARc inhibitors caused microtubule loss by regulating tubulin post-transcriptionally rather than by altering microtubule polymerization or dynamics. Proteasome inhibition by epoxomicin was unable to prevent tubulin loss. siRNA-mediated reduction of PPARc and PPARd proteins did not replicate the effects of PPARc inhibitors or interfere with the inhibitors' effects on apoptosis, cell cycle or tubulin. PPARc inhibitors also reduced CRC cell migration and invasion in assays in vitro and reduced both the number and size of metastases in a HT-29/ SCID xenograft metastatic model of CRC. These results suggest that PPARc inhibitors are a novel potential antimicrotubule therapy for CRC that acts by directly reducing microtubule precursors. ' 2006 Wiley-Liss, Inc.

Colon cancer is one of the most serious complications of inflammatory bowel diseases, especially ulcerative colitis (UC). Previous studies have shown that characteristic immunological event during inflammation in UC is the expression of T helper-type 2 (Th2) cell-derived cytokines. In this study, we investigated the influence of a predominant Th2-type cytokine response in colitis on carcinogen-induced colon tumors. Wild type (WT), interferon gamma (IFN-c) gene deficient (2/2) [Th2 dominant] or interleukin (IL)-4 2/2 [Th1-dominant] mice of BALB/c background were used in this study. To compare tumor formation, mice were given the carcinogen azoxymethane (AOM) and intrarectal administration of trinitrobenzene sulfonic acid (TNBS), to induce colitis. Thirtythree weeks after initial treatment, the total colon was examined. When IFN-c 2/2 mice were treated with AOM and TNBS, significantly higher number of tumors were seen (8.4 6 1.7) than in WT (3.3 6 2.9) or IL-4 2/2 (3.1 6 3.4) mice, which received identical treatments. A separate set of experiment, using less doses of AOM and TNBS also showed the higher frequency of tumor formation in IFN-c 2/2 mice than in IL-4 2/2 mice. Histologically, the tumors were well-or moderately-differentiated adenocarcinomas. No invasion into the submucosal or serosal layers of the intestine was seen. In immunohistological staining, some tumors in IFN-c 2/2 mice showed distinct nuclear expression of b-catenin, in contrast to the strong membrane staining seen in tumors of IL-4 2/2 mice. In conclusion, colonic inflammation associated with Th2-donimant cytokine responses enhanced the formation of malignant neoplasms. ' 2005 Wiley-Liss, Inc.

No abstract