Eukaryotic translation initiation factor 5A2 (eIF5A2) regulates chemoresistance in colorectal cancer through epithelial mesenchymal transition

Abstract

BackgroundChemoresistance is a major obstacle to successful chemotherapy for colorectal cancer. Eukaryotic translation initiation factor 5A2 (eIF5A2), one of the two isoforms in the eIF5A family, has been reported to be a new oncogene in many types of human cancer. In the present study, we aimed to investigate whether eIF5A2 was involved in the chemoresistance to doxorubicin in colorectal cancer.MethodsCell viability was measured by CCK-8 assay with or without doxorubicin treatment. Protein expression was detected by western blot. Tumor cells were transfected with eIF5A2 siRNA or plasmid encoding eIF5A2 to down- or up regulate the expression of eIF5A2.ResultsWe found that eIF5A2-negtive colon cancer cells (HCT116 and HT29) were more sensitive to doxorubicin compare with the eIF5A2-positive cells (LOVO and SW480). Downregulation of eIF5A2 in LOVO and SW480 cells enhanced the chemosensitivity to doxorubicin. On the contrary, overexpression of eIF5A2 reduced doxorubicin sensitivity in colon cancer cells. In addition, eIF5A2 knockdown increased the protein level of E-cadherin and reduced vimentin expression in LOVO and SW480 cells. Meanwhile, upregulation of eIF5A2 potentiated epithelial mesenchymal transition (EMT) in colon cancer cells. Moreover, blockade of EMT with Twist siRNA abolished eIF5A2-regulated chemoresistance in colon cancer cells.ConclusionOur present study demonstrated that eIF5A2 promoted the chemoresistance to doxorubicin via regulation of EMT in colon cancer cells. Therefore, eIF5A2 inhibition may be a new potential strategy for the reversal of drug resistance in colorectal cancer therapy.

The Role of miR‐497/EIF3A Axis in TGFβ1‐Induced Epithelial–Mesenchymal Transition and Extracellular Matrix in Rat Alveolar Epithelial Cells and Pulmonary Fibroblasts

“…In the present study, we demonstrated that a series of doses of TGFβ1 stimulation (2, 5, 10 ng/ml) could promote the protein levels of EIF3A and mesenchymal marker Vimentin, reduce the protein level of epithelial marker E‐cadherin, and the acquisition of an EMT phenotype; shRNA‐induced EIF3A knockdown could suppress TGFβ1‐induced EMT‐related changes, and partially reverse the effect of TGFβ1 on EMT. According to previous studies, eukaryotic translation initiation factor 5A2 (eIF5A2), one of the two isoforms in the eIF5A family, is involved in regulation of the EMT during the chemoresistance to doxorubicin [Bao et al, ]. In our previous study, we demonstrated that EIF3A plays an important role in bleomycin‐induced pulmonary fibrosis by regulating pulmonary fibroblasts’ function, and up‐regulation of eIF3a induced by TGFβ1 is mediated via the ERK1/2 pathway [Li et al, ].…”

“…translation initiation factor 5A2 (eIF5A2), one of the two isoforms in the eIF5A family, is involved in regulation of the EMT during the chemoresistance to doxorubicin [Bao et al, 2015]. In our previous study, we demonstrated that EIF3A plays an important role in bleomycin-induced pulmonary fibrosis by regulating pulmonary fibroblasts' function, and up-regulation of eIF3a induced by TGFb1 is mediated via the ERK1/2 pathway [Li et al, 2015c].…”

<p>The Emerging Roles of miR-125b in Cancers</p>

“…The downregulation of miR-125b causes the overexpression of EIF5A2, which is known to be associated with proliferation and poor prognosis in patients with CRC and NSCLC. 39,[69][70][71] MiR-100 reduces the protein level of Angpt2, which is an essential molecule for angiogenesis, by blocking the mTOR/p70S6K signaling pathway. It has been demonstrated that miR-125b can cause excessive angiogenesis by affecting the proliferation of endothelial cells.…”

Knockdown of EIF5A2 inhibits the malignant potential of non-small cell lung cancer cells

“…Previous studies have demonstrated that EIF5A2 exhibits its tumorigenic effects via activation of the phosphoinositide-3-kinase/Rac-α serine/threonine-protein kinase signaling pathway (15,25) and its induction of matrix metalloproteinase 2 protein expression (26). In addition, EIF5A2 reduces expression of E-cadherin and increases expression of Vimentin (26,27), and may activate transforming protein RhoA precursor/Rac1 signaling pathways (24). Additionally, a previous study identified zinc finger protein Gli1 as a putative transcription factor for EIF5A2 (28).…”