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

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

Author information

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.

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

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