Hedgehog pathway blockade inhibits melanoma cell growth in vitro and in vivo

Kathryn E. O'Reilly, Eleazar Vega Saenz de Miera, Miguel F. Segura, Erica Friedman, Laura Poliseno, Sung Won Han, Judy Zhong, Jiri Zavadil, Anna Pavlick, Eva Hernando, Iman Osman

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Previous reports have demonstrated a role for hedgehog signaling in melanoma progression, prompting us to explore the therapeutic benefit of targeting this pathway in melanoma. We profiled a panel of human melanoma cell lines and control melanocytes for altered expression of hedgehog pathway members and determined the consequences of both genetic and pharmacological inhibition of the hedgehog pathway activator Smoothened (SMO) in melanoma, both in vitro and in vivo. We also examined the relationship between altered expression of hedgehog pathway mediators and survival in a well-characterized cohort of metastatic melanoma patients with prospectively collected follow up information. Studies revealed that over 40% of the melanoma cell lines examined harbored significantly elevated levels of the hedgehog pathway mediators SMO, GLI2, and PTCH1 compared to melanocytes (p < 0.05). SMO inhibition using siRNA and the small molecule inhibitor, NVP-LDE-225, suppressed melanoma growth in vitro, particularly in those cell lines with moderate SMO and GLI2 expression. NVP-LDE-225 also induced apoptosis in vitro and inhibited melanoma growth in a xenograft model. Gene expression data also revealed evidence of compensatory up-regulation of two other developmental pathways, Notch and WNT, in response to hedgehog pathway inhibition. Pharmacological and genetic SMO inhibition also downregulated genes involved in human embryonic stem cell pluripotency. Finally, increased SMO expression and decreased expression of the hedgehog pathway repressor GLI3 correlated with shorter post recurrence survival in metastatic melanoma patients. Our data demonstrate that hedgehog pathway inhibition might be a promising targeted therapy in appropriately selected metastatic melanoma patients.

Original languageEnglish
Pages (from-to)1429-1450
Number of pages22
JournalPharmaceuticals
Volume6
Issue number11
DOIs
Publication statusPublished - 2013 Nov 8

Keywords

  • GLI2
  • Hedgehog
  • Melanoma
  • PTCH1
  • Smoothened

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science

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