| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
[Introduction] Peroxisome proliferator-activated receptor(PPAR) gamma is a ligand-activated transcription factor belonging to the steroid receptor superfamily. Ligand activation of PPAR gamma is known to inhibit the proliferation of various cancer cells. The objective of this study was to determine the inhibitory effect of PPAR gamma ligands on liver metastasis of human colon cancer. [Materials and Methods]PPAR gamma expression was determined in a highly metastatic colon cencer cell lines, HT-29 and SW480, by immunoblotting. The inhibitory effects of a synthetic PPAR gamma ligand, pioglitazone(PGZ), on in vitro cell proliferation of HT-29 and SW480 were measured by cell proliferation assay. The in vivo antitumor effects of PGZ were determined using of severe combined immunodeficient(SCID) mouse xenograft models subcutaneously inoculated with HT-29 and SW480 cells. The inhibitory effects of PGZ on liver metastasis were also assessed using SCID mouse liver metastasis models inoculated in
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to the spleen with HT-29 and SW480 cells according to the number of metastatic nodules and the liver weights. The in vitro and in vivo effects of PGZ on the expression of cyclin D1, cyclooxygenase-2(COX-2), and vascular endothelial growth factor(VEGF), potential targets of PPAR gamma, in HT-29 was determined by immunoblotting and immunohistochemistry. [Results]PPAR gamma was expressed in HT29 and SW480. PGZ inhibited the proliferation of HT-29 and SW480 in vitro both time and dose dependent manners. PGZ also showed in vivo antitumor effects on HT-29 and SW480 in murine xenograft models. PGZ significantly inhibited liver metastasis of HT-29 and SW480 in SCID mouse metastasis models. PGZ also suppressed the expressions of cyclin D1, COX-2, and VEGF in HT-29. [Conclusion]A synthetic PPAR gamma ligand, PGZ, showed both in vitro and in vivo antitumor effects on HT-29 and SW480. The ligands also inhibited liver metastasis of HT-29 and SW480. These effects were possibly mediated by downregulating cyclin D1, COX-2, and VEGF. These data suggest that PPAR gamma may provide a novel target for prevention and treatment of colon cancer metastasis. Less
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