Induction mechanism of apoptosis by troglitazone through peroxisome proliferator-activated receptor-gamma in gastric carcinoma cells.
BACKGROUND
It has been reported recently that the antidiabetic thiazolidinediones not only induce fibroblast differentiation but also inhibit the growth of carcinoma cells.


METHODS
In the present study, in order to elucidate the further mechanism of growth inhibition by troglitazone, the expression of cell cycle regulators and apoptotic regulators were examined by cDNA microarrays and Western blot analysis by gastric carcinoma cells.


RESULTS
Six gastric carcinoma cell lines (TMK-1, MKN-1,7,28,45,74) were treated with 0.1, 1, 10, 100 microM of troglitazone in vitro. The growth of 5 cell lines were inhibited by troglitazone in a time- and dose-dependent manner. Interestingly, the expression of cyclin D mRNA and protein was decreased and that of p27 was increased in TMK-1 cells at 12 hours after troglitazone treatment, suggesting the induction of cell cycle arrest of the cells. On the other hand, DNA ladder formation was observed at 12 hours after treatment. Moreover, the expression of cytochrome C, caspases 3 and 8 and PARP genes was increased after treatment and the gradual reduction of Bcl-XL protein was observed, which indicate that the apoptotic signals were induced after treatment by troglitazone.


CONCLUSIONS
These results suggest that the thiazolidinediones can be a new therapeutic tool for gastric carcinoma via cell cycle regulation and apoptosis.
Yoshida
Kazuhiro
K
Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, School of Medicine, Hiroshima University, Hiroshima, Japan. kyoshida@hiroshima-u.ac.jp
Tanabe
Kazuaki
K
Fujii
Daisuke
D
Oue
Naohide
N
Yasui
Wataru
W
Toge
Tetsuya
T
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008024:Ligands; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics; D047488:Retinoid X Receptors; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002839:Chromans; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone