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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.

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Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden. Electronic address:


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.


GLI1 oncogene; Hedgehog signaling; Mouse xenograft; RNA-sequencing; Small molecule inhibitor

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