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Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo
Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
Laboratory of Translational Research in Childhood Cancer, Vall d'Hebron Research Institute, Barcelona 08035, Spain
Department of Surgery, New York University School of Medicine, New York, NY 10016, USA
Oncogenomics Unit, Core Research Laboratory, Istituto Toscano Tumori, Pisa 56124, Italy
Department of Population Health, New York University School of Medicine, New York, NY 10016, USA
NYU Center for Health Informatics and Bioinformatics, New York University Langone Medical Center, New York, NY 10016, USA
International Agency for Research on Cancer, 69372 Lyon Cedex 08, France
Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
* Author to whom correspondence should be addressed.
Received: 3 September 2013; in revised form: 24 October 2013 / Accepted: 31 October 2013 / Published: 11 November 2013
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.
Keywords: melanoma; hedgehog; Smoothened; GLI2; PTCH1
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O'Reilly, K.E.; de Miera, E.V.-S.; Segura, M.F.; Friedman, E.; Poliseno, L.; Han, S.W.; Zhong, J.; Zavadil, J.; Pavlick, A.; Hernando, E.; Osman, I. Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo. Pharmaceuticals 2013, 6, 1429-1450.
O'Reilly KE, de Miera EV-S, Segura MF, Friedman E, Poliseno L, Han SW, Zhong J, Zavadil J, Pavlick A, Hernando E, Osman I. Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo. Pharmaceuticals. 2013; 6(11):1429-1450.
O'Reilly, Kathryn E.; de Miera, Eleazar V.-S.; Segura, Miguel F.; Friedman, Erica; Poliseno, Laura; Han, Sung W.; Zhong, Judy; Zavadil, Jiri; Pavlick, Anna; Hernando, Eva; Osman, Iman. 2013. "Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo." Pharmaceuticals 6, no. 11: 1429-1450.