Skip to main content
main-content

01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Experimental & Clinical Cancer Research 1/2018

ERRα suppression enhances the cytotoxicity of the MEK inhibitor trametinib against colon cancer cells

Zeitschrift:
Journal of Experimental & Clinical Cancer Research > Ausgabe 1/2018
Autoren:
Sheng Zhou, Hongwei Xia, Huanji Xu, Qiulin Tang, Yongzhan Nie, Qi yong Gong, Feng Bi
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13046-018-0862-8) contains supplementary material, which is available to authorized users.
Sheng Zhou, Hongwei Xia and Huanji Xu contributed equally to this work.

Abstract

Background

ERRα, 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.

Methods

The 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.

Results

ERRα 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.

Conclusions

The 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.
Zusatzmaterial
Additional file 2: Figure S2. Suppression of ERRα completely reduces the EGF treatment-induced cell proliferation and enhances the cytotoxicity of trametinib. a WB for ERRα, c-Myc, cyclin D1, pERK and ERK in the SW1116 cells treated with EGF (20/μl) at the indicated times (0.5, 2, 4, 6 and 8 h) in serum-free medium. b CCK-8 assay for the HCT116 and SW480 cells cultured with si-NC or si-ERRα (or/and 20 ng/μl EGF) for 3 d (* P< 0.05; ** P< 0.01; *** P< 0.001). The data are presented as the mean±SD of the experiments performed in triplicate. c WB for ERRα, c-Myc and cyclin D1 in the HCT116 and SW480 cells treated with si-NC or si-ERRα (or/and 20 ng/μl EGF) in serum-free medium for 48 h. d WB for pERK and ERK in the HCT116, SW480 and SW1116 cells treated with the indicated concentrations of trametinib (0–100 nM) or DMSO for 48 h. e WB for ERRα, c-Myc and cyclin D1 in the SW1116 cells treated with DMSO or 10 nM trametinib (or/and 20 ng/μl EGF) for 48 h. f CCK-8 assay for the HCT116 and SW480 cells treated with si-ERRα (or/and 50 nM trametinib) for 3 d. g, h, i WB for ERRα, IDH3A, c-Myc and Cyclin D1 in the HCT116, SW480 and SW1116 cells treated with si-ERRα (or/and 50 nM trametinib) for 2 d. j WB for ERRα in the HCT116 and SW1116 cells treated with cycloheximide (10 μg/ml) or trametinib combined with cycloheximide in a time-course experiment. k WB for ERRα in the HCT116 and SW1116 treated with trametinib (50 nM, 48 h) or DMSO supplemented with or without MG132 (10 μM) for 8 h. (PDF 898 kb)
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Zur Ausgabe

Neu im Fachgebiet Onkologie

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Onkologie und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise