Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma.

Abstract

PURPOSE:

The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown.

METHODS:

Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both in vitro and in vivo xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays.

RESULTS:

We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling.

CONCLUSIONS:

Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.

• Authors: Jinpeng Zhou, Yang Jiang, Junshuang Zhao, Haiying Zhang, Jinlong Fu, Peng Luo, Yanju Ma, Dan Zou, Huiling Gao, Jiangfeng Hu, Ye Zhang, Zhitao Jing
• Journal: Cellular oncology (Dordrecht) (Cell Oncol (Dordr)) Vol. 43 Issue 3 Pg. 461-475 (Jun 2020) ISSN: 2211-3436 [Electronic] Netherlands
• PMID: 32207044 (Publication Type: Journal Article)

Chemical References

• Interleukin-6
• Iron Chelating Agents
• NDRG2 protein, human
• Nuclear Receptor Subfamily 1, Group F, Member 1
• RORA protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• Thiosemicarbazones
• Tumor Suppressor Proteins
• di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone
• JAK2 protein, human
• Janus Kinase 2

Topics

• Animals
• Apoptosis (drug effects)
• Carcinogenesis (drug effects, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Glioma (pathology)
• Humans
• Interleukin-6 (metabolism)
• Iron Chelating Agents (pharmacology)
• Janus Kinase 2 (metabolism)
• Mice, Inbred BALB C
• Models, Biological
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Nuclear Receptor Subfamily 1, Group F, Member 1 (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Thiosemicarbazones (pharmacology)
• Transcription, Genetic (drug effects)
• Tumor Suppressor Proteins (genetics, metabolism)