PPARγ inhibitors reduce tubulin protein levels by a PPARγ, PPARδ and proteasome‐independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells

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.

Disruption of ERα signalling pathway by PPARγ agonists: evidences of PPARγ-independent events in two hormone-dependent breast cancer cell lines

“…Two of these antagonists, T0070907 and BADGE, potentiated ERa proteolysis in case of co-treatment with TGZ while GW9662 did not. This potentiation could explain the cell growth inhibitory effects of these compounds recently reported in the T47D breast cancer cell line and colorectal carcinoma cells [53][54][55].…”

A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

“…1C), a leading experimental chemopreventive compound against colon cancer that inhibits intestinal tumors in APC min mice (17). We expect that therapeutic concentration of FH535 can be achieved in mice because T0070907 was shown to reduce the metastasis of injected cancerous cells in mice (44) and GW9662 suppressed mice obesity induced by a high-fat diet (45).…”

Computational identification of surrogate genes for prostate cancer phases using machine learning and molecular network analysis

“…In fact, the respective relationships between both tubulin and GJIC with metastasis of prostate/other cancers have been studied. For instance, the level of tubulin affects the metastasis of colorectal carcinoma cells [31]; and breakdowns of GJIC in a variety of cancer cells correlate their metastatic capacity [32-34]. Moreover, studies have also indicated that TUBB6 itself is functionally related with the metastasis of various cancers.…”