Differentiation-inducing factor-1 suppresses the expression of c-Myc in the human cancer cell lines.
Differentiation-inducing factor-1 (DIF-1), a morphogen for Dictyostelium discoideum, inhibits the proliferation of human cancer cell lines by suppressing the Wnt/β-catenin signaling pathway. In this study, we examined the effect of DIF-1 on c-Myc, a target gene product of the Wnt/β-catenin signaling pathway, mainly using HCT-116 colon cancer cells. DIF-1 strongly reduced the amount of c-Myc protein in time- and concentration-dependent manners and reduced c-Myc mRNA expression by inhibiting promoter activity through the TCF binding sites. The effect of DIF-1 on c-Myc was also confirmed using the human cervical cell line HeLa. Pretreatment with the proteasome inhibitor MG132 or glycogen synthase kinase-3β (GSK-3β) inhibitors (LiCl and SB216763) attenuated the effect of DIF-1, suggesting that DIF-1 induced c-Myc protein degradation through GSK-3β activation. Furthermore, we examined whether c-Myc was involved in the anti-proliferative effect of DIF-1 using c-Myc-overexpressing cells and found that c-Myc was associated with the anti-proliferative effect of this compound. These results suggest that DIF-1 inhibits c-Myc expression by inhibiting promoter activity and inducing protein degradation via GSK-3β activation, resulting in the inhibition of cell proliferation. Since c-Myc seems to be profoundly involved in accelerated proliferation of various malignant tumors, DIF-1 may have a potential to develop into a novel anti-cancer agent.
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Kentaro
K
Jingushi
Toshihisa
T
Nakamura
Fumi
F
Takahashi-Yanaga
Etsuko
E
Matsuzaki
Yutaka
Y
Watanabe
Tatsuya
T
Yoshihara
Sachio
S
Morimoto
Toshiyuki
T
Sasaguri
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006588:Hexanones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
C490570:Differentiation-inducing factor-1, Dictyostelium; D004791:Enzyme Inhibitors; D006588:Hexanones; D006843:Hydrocarbons, Chlorinated; D007211:Indoles; D007976:Leupeptins; D008301:Maleimides; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C417521:SB 216763; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde