Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands inhibit the growth of PPAR-gamma expressing cancer cells through terminal differentiation. However, there are few studies examining the effect of a PPAR-gamma ligand on metastatic potential of cancer cells in an animal model and the underlying molecular mechanisms. We have recently developed a rectal cancer xenograft animal model in which anti-tumor and anti-metastatic efficacy of agents can be evaluated. This study was designed to examine whether a representative PPAR-gamma ligand, thiazolidinedione (TZD), could inhibit growth and metastasis of PPAR-gamma positive HT-29 human colon cancer cells through the induction of terminal differentiation. TZD caused G1 arrest in association with a marked increase in p21Waf-1, Drg-1, and E-cadherin expression. In untreated cancer cells, fluorescence immunostaining demonstrated beta-catenin in the nucleus and/or cytoplasm; in TZD-treated cancer cells, beta-catenin localization shifted to the plasma membrane, in association with increased E-cadherin at this site and reduced tyrosine phosphorylation of beta-catenin. In addition, TZD completely inhibited lymph node and lung metastases in the xenograft animal model, and TZD inhibited growth of primary xenografts by 40%. These results suggest that TZD can function as a cytostatic anti-cancer agent to inhibit growth and metastasis of HT-29 colon cancer cells through differentiation-promoting effects. These effects involve not only modulation of the E-cadherin/beta-catenin system, but also up-regulation of Drg-1 gene expression.
Department of Surgical Oncology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-0934, Japan.
Tetsuya
T
Yoshizumi
Tetsuo
T
Ohta
Itasu
I
Ninomiya
Itsuro
I
Terada
Sachio
S
Fushida
Takashi
T
Fujimura
Gen-Ichi
G
Nishimura
Koichi
K
Shimizu
Shuangqin
S
Yi
Koichi
K
Miwa
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015820:Cadherins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D042541:Intracellular Space / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D047495:PPAR gamma / Q000819:agonists*; D016160:Retinoblastoma Protein / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D000970:Antineoplastic Agents; D015820:Cadherins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047495:PPAR gamma; D016160:Retinoblastoma Protein; D045162:Thiazolidinediones; D015534:Trans-Activators; D051176:beta Catenin; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C493956:CDKN1A protein, human; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C493957:Cdkn1a protein, mouse; C089946:2,4-thiazolidinedione