Role of the novel NDRG1-MIG6 axis in down-regulating the epidermal growth factor receptor and other tyrosine kinases

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Richardson, Des
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2021
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Hiroshima, Japan

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Abstract

N-myc downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-beta pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells.

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Cancer Science

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112

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S1

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Oncology and carcinogenesis

Pharmacology and pharmaceutical sciences

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Life Sciences & Biomedicine

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Richardson, D, Role of the novel NDRG1-MIG6 axis in down-regulating the epidermal growth factor receptor and other tyrosine kinases, Cancer Science, 2021, 112 (S1), pp. 996-996