Loss of XIAP sensitizes colon cancer cells to PPARγ independent antitumor effects of troglitazone and 15-PGJ2
Introduction
XIAP (X-linked inhibitor of apoptosis protein) is a member of the IAP (inhibitor of apoptosis protein) family that functions as a potent endogenous inhibitor of apoptosis [1], [2], [3], [4], [5]. Selectively targeting cancer cells for apoptosis can be a promising approach for cancer therapy. Recent studies have indicated that XIAP may have a great potential in cancer gene therapy [6]. However, as cancer development is such a complex biological process involving numerous genes and pathways that regulate apoptosis, proliferation, and angiogenesis, targeting XIAP alone may not be potent enough for cancer control. Consequently, combinational therapeutic approaches may worth exploring [7].
Peroxisome proliferator-activated receptor gamma (PPARγ) is an important member of a superfamily of nuclear hormone receptors. It functions as a transcription factor and is widely expressed in many human tissues including but not limited to adipose tissues, normal colonic mucosa, duodenal mucosa, endothelial cells, liver, and small intestine [8], [9], [10], [11]. Binding of PPARγ ligands to PPARγ receptor leads to a heterodimerization of PPARγ with the retinoid X receptor (RXR) which then binds to peroxisome response elements (PPRE), leading to transcription of downstream target genes. Studies have showed that ligand-induced activation of PPARγ induces cell differentiation and apoptosis in a variety of cancers including colon cancer cells [12], [13], [14], [15], [16], [17]. Some natural PPARγ ligands such as conjugated linoleic acid have been showed to inhibit peritoneal metastasis of gastrointestinal cancers [18], [19]. Activation of PPAR γ has also been reported to suppress angiogenesis in cancers [20]. These results highly suggest that PPARγ ligands may be potentially useful as anticancer or chemoprevention agents for colon cancer. However, using PPARγ ligands as a monotherapy for cancer only have limited efficacy. Furthermore, the effect of PPAR γ ligands on colon cancer is rather controversial. Activation of PPAR γ by its ligands was found to promote the growth of colon cancer in some studies [21], [22], [23]. More recently, large body of evidence indicates that specific ligands for PPARγ may exert their effect independent of PPARγ receptor [13], [24], [25], [26], [27], [28], [29]. The fact that the same PPARγ ligand may exert different effect in different subtypes of a particular cell line [30], or different PPARγ ligands exert different effects in the same cell line [31], [32] further suggest that mechanisms other than PPARγ receptor may be responsible for the anticancer effect of PPARγ ligands.
We were interested in exploring whether combinational targeting XIAP and PPARγ would offer a better therapeutic benefit for colon cancer. In our recent studies, we observed that a combination of XIAP down-regulation and PPARγ activation exhibited a stronger anticancer effect in colon cancer [33].
In this study, we aimed to elucidate the molecular mechanisms by which the combination of XIAP down-regulation and PPARγ activation exerts anticancer effects against colon cancer. In particular, we will evaluate whether the anticancer effect is dependent upon PPARγ receptor.
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Chemicals, reagents, and cell lines
Troglitazone, 15-deoxy-Δ12,14-prostaglandin (15-PGJ2), GW9662, and PPARγ Transcription Factor Assay Kit were purchased from Cayman Chemicals (Ann Arbor, MI). Human colon cancer cell lines HCT116 cells with wild type and XIAP knockout phenotypes (HCT116-XIAP+/+, HCT116-XIAP−/−) were kindly provided by Professor Bert Vogelstein (Howard Hughes Medical Institute & Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, USA) [34]. All culture-related materials were
Expression of XIAP and PPARγ in colon cancer tissues by immunohistochemistry and Western blot
In the 2 microarray slides containing 140 pairs of colon cancer tissues and matched non-cancerous tissues, immunohistochemical staining showed that XIAP was positive in 41% of colon cancer tissues and 9% of non-cancerous tissues. Among the XIAP positive colon cancer tissues, 63% had strong expression (defined as score ⩾ 3). For PPARγ, non-cancerous and colon cancer tissues exhibited similar expression positivity: 42.9% vs 42.6%, respectively. Among these cases, 61% of cancer tissues and 21% of
Discussion
In this study, we found that the expression levels of XIAP and PPARγ in cancer tissues exceeded that of the matched non-cancerous colonic tissues, but the PPARγ transcriptional activity is significantly reduced in cancer tissues. This novel finding may suggest that a reduced activity of PPARγ may be related to colon cancer development. This finding is consistent with the previous results by others that PPARγ may act as a tumor suppressor gene [12], [38], [39]. The observed over-expression of
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