Peroxisome proliferator-activated receptor γ ligands suppress colon carcinogenesis induced by azoxymethane in mice

Osawa, Emi; Nakajima, Atsushi; Wada, Koichiro; Ishimine, Satoko; Fujisawa, Nobutaka; Kawamori, Toshihiko; Matsuhashi, Nobuyuki; Kadowaki, Takashi; Ochiai, Masako; Sekihara, Hisahiko; Nakagama, Hitoshi

doi:10.1053/gast.2003.50067

Cited by 175 publications

(167 citation statements)

References 15 publications

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“…28 We recently observed that downregulation of XIAP greatly enhanced the antitumor effects of troglitazone. Others have recently reported that rosiglitazone could synergisti- cally enhance the antitumor effect of certain anticancer drugs, 16 and promising results have been reported in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

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Ligands for peroxisome proliferator-activated receptor gamma (PPARc) possess anticancer properties. However, the efficacy of PPARc ligands varies in different cancers. In colon cancer, the role of PPARc and its ligands is controversial. We recently showed that downregulation of X-linked inhibitor of apoptosis protein (XIAP) could sensitize colon cancer cells to troglitazone, and 15-deoxy-D12,14-prostaglandin J2 (15-PGJ2) induced cell killing. In our study, we aimed to examine whether rosiglitazone, another more clinically relevant PPARc ligand, has any synergistic anticancer effect with XIAP downregulation in colon cancer. Human colon cancer cell lines HCT116-XIAP 1/1 cells and HCT116-XIAP 2/2 cells were treated with various concentrations of rosiglitazone. The effects of rosiglitazone on cell proliferation, apoptosis and growth of xenograft colon cancers were studied. Rosiglitazone barely suppressed the growth and only very weakly induced apoptosis in HCT116 cells in vitro. Loss of XIAP did not sensitize HCT116 cells to rosiglitazone-induced growth inhibition or apoptosis. In vivo studies revealed that rosiglitazone strongly suppressed the growth of xenograft colon cancer, especially tumors derived from HCT116-XIAP 2/2 cells. The rosiglitazone-treated tumor had reduced expression of ki-67 and lowered mitotic rate. Downregulation of XIAP was associated with an impaired activation of PPARc by its ligand. Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP 2/2 cells, as well as in xenograft tumors derived from HCT116-XIAP 2/2 cells. We concluded that rosiglitazone significantly suppresses the growth of xenograft colon cancer, and downregulation of XIAP sensitizes the xenograft tumors to rosiglitazone-induced tumor suppression in vivo via upregulation of PTEN.

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Section: Discussionmentioning

confidence: 99%

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

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“…mPGES-1 deficiency also resulted in the activation of the PPARg pathway and suppression of the NF-kB pathway in AOM-induced colon carcinogenesis (Figure 3). Reportedly, PPARg agonists significantly suppress AOM-induced colon carcinogenesis (Osawa et al, 2003) and act as potent inductors of growth arrest and apoptotic cell death in cancers, including colon cancer (Thompson, 2007). On the other hand, activation of NF-kB is associated with cell proliferation, cell cycle progression, tumor growth promotion, angiogenesis and metastasis through the expression of genes participating in malignant conversion and tumor promotion (Garg and Aggarwal, 2002).…”

Section: Mpges-1 Promotes Colon Carcinogenesismentioning

confidence: 99%

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

et al. 2011

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Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E 2 is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE 2 -biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of b-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D 2 and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MUs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MUs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MUs failed to facilitate tumor growth. The adoptive transfer of WT BM-MUs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MUs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.

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“…Several nuclear receptors including PPAR␥, RAR, and their heterodimeric partner RXR have been recognized as negative regulators for breast and colon cancers, and their ligands have been demonstrated as potential chemopreventative agents for breast and colon carcinogenesis (43)(44)(45)(46)(47)(48)(49). AIB3 interacts with and coactivates PPAR␥, RAR, and RXR in the presence of their active ligands (9,(11)(12)(13).…”

Section: Mammary Tumorigenesis In Aib3mentioning

confidence: 99%

Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor γ and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice

et al. 2004

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Peroxisome proliferator-activated receptor γ ligands suppress colon carcinogenesis induced by azoxymethane in mice

Cited by 175 publications

References 15 publications

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor γ and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice

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