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.
Keywords:
GLI1 oncogene; Hedgehog signaling; Mouse xenograft; RNA-sequencing; Small molecule inhibitor.
Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cerebellar Neoplasms / drug therapy*
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Cerebellar Neoplasms / enzymology
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Cerebellar Neoplasms / genetics
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Cerebellar Neoplasms / pathology
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Female
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Furans / pharmacology*
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Medulloblastoma / drug therapy*
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Medulloblastoma / enzymology
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Medulloblastoma / genetics
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Medulloblastoma / pathology
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Mice, Nude
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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Rhabdomyosarcoma / drug therapy*
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Rhabdomyosarcoma / enzymology
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Rhabdomyosarcoma / genetics
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Rhabdomyosarcoma / pathology
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Signal Transduction / drug effects
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Tumor Burden / drug effects
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Xenograft Model Antitumor Assays
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Zinc Finger Protein GLI1 / analysis
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Zinc Finger Protein GLI1 / genetics
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Zinc Finger Protein GLI1 / metabolism*
Substances
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Antineoplastic Agents
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Furans
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GANT 61
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GLI1 protein, human
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Hedgehog Proteins
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NSC 652287
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Pyridines
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Pyrimidines
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TP53 protein, human
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Tumor Suppressor Protein p53
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Zinc Finger Protein GLI1
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JNK Mitogen-Activated Protein Kinases