GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis.

Abstract

Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.

• Authors: Ritesh K Srivastava, Samer Zaid Kaylani, Nayf Edrees, Changzhao Li, Sarang S Talwelkar, Jianmin Xu, Komaraiah Palle, Joseph G Pressey, Mohammad Athar
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 23 Pg. 12151-65 (Dec 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25432075 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• GANT 61
• Hedgehog Proteins
• Oncogene Proteins
• Pyridines
• Pyrimidines
• SHH protein, human
• Trans-Activators
• Zinc Finger Protein GLI1
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Flow Cytometry
• Fluorescent Antibody Technique
• Hedgehog Proteins (metabolism)
• Humans
• Immunohistochemistry
• Mice
• Mice, Nude
• Oncogene Proteins (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Rhabdomyosarcoma, Alveolar (metabolism, pathology)
• Rhabdomyosarcoma, Embryonal (metabolism, pathology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Trans-Activators (antagonists & inhibitors)
• Xenograft Model Antitumor Assays
• Zinc Finger Protein GLI1