Tumor necrosis factor α (TNFα) plays a vital role in cancer progression as it is associated with inflammation and promotion of cancer angiogenesis and metastasis. The effects of TNFα are mediated by its downstream target, the oncogene lysine-rich CEACAM1 coisolated protein (LYRIC, also known as metadherin or astrocyte elevated gene-1). LYRIC plays an important role in activating the nuclear factor-ĸB (NF-κB) signaling pathway, which controls multiple cellular processes, including proliferation, apoptosis, migration, etc. In contrast, the metastasis suppressor N-myc downstream regulated gene 1 (NDRG1) has the opposite effect on the NF-κB pathway, being able to inhibit NF-κB activation and reduce angiogenesis, proliferation, migration, and cancer cell invasion. These potent anticancer properties make NDRG1 an ideal therapeutic target. Indeed, a novel class of thiosemicarbazone anticancer agents that target this molecule has been developed; the lead agent, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, has recently entered clinical trials for advanced and resistant cancers. To further elucidate the interaction between NDRG1 and oncogenic signaling, this study for the first time assessed the effects of NDRG1 on the tumorigenic properties of TNFα and its downstream target, LYRIC. We have demonstrated that NDRG1 inhibits the TNFα-mediated epithelial-to-mesenchymal transition. Further, NDRG1 also potently inhibited LYRIC expression, with a negative feedback loop existing between these two molecules. Examining the mechanism involved, we demonstrated that NDRG1 inhibited phosphatidylinositol 3-kinase/AKT signaling, leading to reduced levels of the LYRIC transcriptional activator, c-Myc. Finally, we demonstrated that novel thiosemicarbazones that upregulate NDRG1 also inhibit LYRIC expression, further highlighting their marked potential for cancer treatment.
- Received December 13, 2016.
- Accepted March 7, 2017.
R.X. and I.H.Y.P. contributed equally to this work.
D.R.R. and Z.K. contributed equally as senior/corresponding authors.
This work was supported by a scholarship from the National Natural Science Foundation of China [Grant 81272775]; a Student Attachment Program Scholarship from the Hong Kong Polytechnic University; Australian Postgraduate Awards from the University of Sydney; a Senior Principal Research Fellowship [Grant 1062607], Peter Doherty Early Career Fellowships [Grants 1037323, 1074033], a R.D. Wright Career Development Fellowship [Grant 1083057], and Project Grants from the National Health and Medical Research Council of Australia [Grant 1060482]; Cancer Australia and Cure Cancer Australia priority-driven collaborative cancer research scheme [Grant 1086449]; and a Cancer Institute New South Wales Early Career Fellowship [Grant 12-ECF2-17].
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics