Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo

• DOI: 10.3390/ph6111429
• Publication Date: 2013-11-11T17:41:10Z
• Authors: Kathryn O'Reilly; Eleazar De Miera; Miguel Segura; Erica Friedman; Laura Poliseno; Sung Han; Judy Zhong; Jiri Zavadil; Anna Pavlick; Eva Hernando; Iman Osman
• Keywords: Smoothened; 0301 basic medicine; PTCH1; hedgehog; GLI2; R; Article; 3. Good health; RS1-441; 03 medical and health sciences; melanoma; hedgehog; Smoothened; GLI2; PTCH1; Pharmacy and materia medica; melanoma; Medicine

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