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6-Thioguanine inhibition of parathyroid hormone-related protein expression is mediated by GLI2.

Johnson RW, Merkel AR, Danilin S, Nguyen MP, Mundy GR, Sterling JA
Anticancer Res. 2011 31 (9): 2705-12

PMID: 21868511 · PMCID: PMC3430074

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 AND METHODS - 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.

MeSH Terms (10)

Cell Line, Tumor Cell Proliferation Humans Kruppel-Like Transcription Factors Nuclear Proteins Parathyroid Hormone-Related Protein Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Thioguanine Zinc Finger Protein Gli2

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