RITA downregulates Hedgehog-GLI in medulloblastoma and rhabdomyosarcoma via JNK-dependent but p53-independent mechanism.

Abstract

Overactivation of the Hedgehog (HH) signaling pathway is implicated in many cancers. In this study, we demonstrate that the small molecule RITA, a p53 activator, effectively downregulates HH signaling in human medulloblastoma and rhabdomyosarcoma cells irrespective of p53. This is mediated by a ROS-independent activation of the MAP kinase JNK. We also show that in vitro RITA sensitized cells to the GLI antagonist GANT61, as co-administration of the two drugs had more pronounced effects on cell proliferation and apoptosis. In vivo administration of RITA or GANT61 suppressed rhabdomyosarcoma xenograft growth in nude mice; however, co-administration did not further enhance tumor suppression, even though cell proliferation was decreased. RITA was more potent than GANT61 in downregulating HH target gene expression; surprisingly, this suppressive effect was almost completely eliminated when the two drugs were administered together. Notably, RNA-seq demonstrated a broader response of pathways involved in cancer cell growth in the combination treatment, providing a plausible interpretation for tumor reduction in the absence of HH signaling downregulation.

• Authors: Ani Azatyan, Gabriel Gallo-Oller, Yumei Diao, Galina Selivanova, John Inge Johnsen, Peter G Zaphiropoulos
• Journal: Cancer letters (Cancer Lett) Vol. 442 Pg. 341-350 (02 01 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30447254 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Furans
• GANT 61
• GLI1 protein, human
• Hedgehog Proteins
• NSC 652287
• Pyridines
• Pyrimidines
• TP53 protein, human
• Tumor Suppressor Protein p53
• Zinc Finger Protein GLI1
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cerebellar Neoplasms (drug therapy, enzymology, genetics, pathology)
• Female
• Furans (pharmacology)
• Hedgehog Proteins (genetics, metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Medulloblastoma (drug therapy, enzymology, genetics, pathology)
• Mice, Nude
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Rhabdomyosarcoma (drug therapy, enzymology, genetics, pathology)
• Signal Transduction (drug effects)
• Tumor Burden (drug effects)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays
• Zinc Finger Protein GLI1 (analysis, genetics, metabolism)