Abstract
BackgroundERRα, a constitutive transcription factor that regulates energy metabolism, plays an important role in the progression of various tumours. However, its role in cell survival and proliferation and its implication in targeted therapy in colon cancer remains elusive.MethodsThe expression of ERRα in colon cancer tissues and cell lines was detected by using western blotting and immunohistochemistry. A wound healing assay and a transwell assay were performed to examine the migration and invasion of the colon cancer cells. A cell viability assay, clonogenic assay, western blot assay and the dual-luciferase reporter assay were employed to study the interaction between trametinib (inhibitor of MEK) and EGF treatment. Flow cytometry, western blotting, quantitative reverse-transcription polymerase chain reaction and xenograft studies were used to identify whether the combination of trametinib and simvastatin had a synergistic effect.ResultsERRα positively regulated the cell proliferation, migration and invasion of colon cancer cells, and the suppression of ERRα completely reduced the EGF treatment-induced proliferation of colon cancer cells. Further investigation showed that trametinib partially restrained the up-regulation of ERRα induced by the EGF treatment, and ERRα inhibition increased the sensitivity of colon cancer cells to trametinib. At last, we combined trametinib with simvastatin, a common clinically used drug with a new reported function of transcriptional activity inhibition of ERRα, and found that this combination produced a synergistic effect in inhibiting the proliferation and survival of colon cancer cells in vitro as well as in vivo.ConclusionsThe present data indicated that ERRα acted as an oncogene in colon cancer cells, and the combined targeting of ERRα and MEK might be a promising therapeutic strategy for colon cancer treatment.
Highlights
Oestrogen-related receptor α (ERRα), a constitutive transcription factor that regulates energy metabolism, plays an important role in the progression of various tumours
The results revealed that the cellular growth and colony information were strongly inhibited in the HCT116 and SW480 cells with shERRα#1 or shERRα#2 transfection compared with the cells transfected with the control shRNA (Figs. 1d-e, 2e-f )
(See figure on previous page.) Fig. 5 Antitumour effect of the combination of trametinib and simvastatin. a Cell proliferation assays at day 3 for the HCT116 and SW480 cells cultured with simvastatin (10 μM) or dimethyl sulfoxide (DMSO) in the presence or absence of 50 nM trametinib. b, c Clonogenic assays and qualitative analysis of the HCT116 and SW480 cells cultured with DMSO or 10 μM simvastatin at day 7. d Quantitative real-time PCR analysis of ERRα and Isocitrate Dehydrogenase 3) Alpha (IDH3A), c-Myc, cyclin D1 in the HCT116 cells treated with 10 μM simvastatin for 48 h
Summary
ERRα, a constitutive transcription factor that regulates energy metabolism, plays an important role in the progression of various tumours. Various target drugs, including cetuximab, bevacizumab and regorafinib, are widely used in colon cancer and are involved in targeting the EGFR signalling molecules. A number of preclinical therapeutic strategies have been developed by combining EGFR pathway inhibitors with other target drugs in BRAF/KRAS mutant colon cancers [5,6,7]. None of these have been approved for clinical use because of
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