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

Ani Azatyan; Gabriel Gallo-Oller; Yumei Diao; Galina Selivanova; John Inge Johnsen; Peter G Zaphiropoulos

doi:10.1016/j.canlet.2018.11.005

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.

Authors

Ani Azatyan¹, Gabriel Gallo-Oller², Yumei Diao¹, Galina Selivanova³, John Inge Johnsen², Peter G Zaphiropoulos⁴

Affiliations

¹ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
² Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden.
³ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
⁴ Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden. Electronic address: peter.zaphiropoulos@ki.se.

PMID: 30447254
DOI: 10.1016/j.canlet.2018.11.005

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