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

Rachelle W. Johnson, Alyssa R. Merkel, Danilin Sabrina, Mai P. Nguyen, Gregory R. Mundy, Julie A. Sterling

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 GL12 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 GL12 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 GL12, 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.

Original languageEnglish (US)
Pages (from-to)2705-2712
Number of pages8
JournalAnticancer Research
Volume31
Issue number9
StatePublished - Sep 2011
Externally publishedYes

Keywords

  • 6-thioguanine
  • Breast cancer
  • GLI2
  • Osteolysis
  • PTHrP

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