6-Thioguanine inhibition of parathyroid hormone-related protein expression is mediated by GLI2.
Anticancer Res
; 31(9): 2705-12, 2011 Sep.
Article
en En
| MEDLINE
| ID: mdl-21868511
ABSTRACT
BACKGROUND:
Breast cancer cells frequently metastasize to bone, where they up-regulate their expression of the transcription factor GLI2 and the downstream osteolytic factor parathyroid hormone-related protein (PTHrP). The guanosine nucleotide 6-thioguanine (6-TG) inhibits PTHrP expression and blocks osteolytic bone destruction in mice inoculated with bone metastatic cells; however, the mechanism by which 6-TG inhibits PTHrP remains unclear. We hypothesized that 6-TG inhibition of PTHrP is mediated through GLI2 signaling. MATERIALS ANDMETHODS:
Human MDA-MB-231 breast cancer cells and RWGT2 squamous-cell lung carcinoma cells were treated with 100 µM 6-TG and examined for GLI2 mRNA expression and stability by Q-PCR, promoter activity by luciferase assay, and protein expression by Western blot.RESULTS:
6-TG significantly blocked GLI2 mRNA and protein expression, but did not affect stability. Additionally, 6-TG directly inhibited GLI2 promoter activity, and when cells were transfected with constitutively expressed GLI2, the inhibitory effect of 6-TG on PTHrP expression was abolished.CONCLUSION:
Taken together, these data indicate that 6-TG regulates PTHrP in part through GLI2 transcription, and therefore the clinical use of 6-TG or other guanosine nucleotides may be a viable therapeutic option in tumor types expressing elevated levels of GLI proteins.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tioguanina
/
Proteínas Nucleares
/
Proteína Relacionada con la Hormona Paratiroidea
/
Factores de Transcripción de Tipo Kruppel
Límite:
Humans
Idioma:
En
Revista:
Anticancer Res
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
GR
/
GRECIA
/
GREECE
/
GRÉCIA