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

Cancer Lett. 2019 Feb 1;442:341-350. doi: 10.1016/j.canlet.2018.11.005. Epub 2018 Nov 14.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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