eIF4E promotes tumorigenesis and modulates chemosensitivity to cisplatin in esophageal squamous cell carcinoma

Abstract

Patients with esophageal squamous cell cancer are often diagnosed with advanced diseases that respond poorly to chemotherapy. Overexpression of eIF4E leads to enhance the translation of key malignancy-related proteins and enabling tumor growth and chemoresistance in a variety of human malignancies, but whether it has a role in ESCC remains obscure. We hypothesized that eIF4E promoted ESCC tumorigenesis and facilitated the development of acquired resistance to the cisplatin-based chemotherapy. In this study, we showed that eIF4E expression was increased significantly in clinical ESCC tissues and and ESCC cell lines and its expression level was correlated with lymph node metastasis, TNM stage, as well as overall and disease-free survival of ESCC. We also showed here that knockdown of eIF4E in EC9706 would dramatically reduced cell proliferation, colony formation, migration and invasion, apoptosis in vitro as well as in vivo, and vice versa. Moreover, “weak mRNAs” were demonstrated to be regulated by eIF4E in ESCC, which might interpret the above function. Overexpression of eIF4E decreased the efficacy of cisplatin-induced cell growth inhibition in ESCC cell line and xenograft model (P < 0.05). eIF4E knockdown by shRNA increased cisplatin-induced cytotoxicity in ESCC cell lines, and enhanced chemosensitivity to cisplatin in xenograft tumor models. Furthermore, we found that the PI3K/AKT pathway and Bcl-2/Bax ratio might be responsible for the eIF4E-induced cisplatin resistance in ESCC. Our data collectively show association of eIF4E expression with chemotherapeutic response in ESCC, and suggest that therapeutically targeting eIF4E may be a viable means of improving chemotherapy response in ESCC.

MCM7 amplification and overexpression promote cell proliferation, colony formation and migration in esophageal squamous cell carcinoma by activating the AKT1/mTOR signaling pathway

“…In recent studies, the phosphorylation of AKT was shown correlated with poor prognosis in ESCC (31,32). AKT was responsible for the cisplatin resistance, and could promote metastasis of ESCC by targeting epithelial-mesenchymal transition (33)(34)(35). mTOR activation was able to also prcomote the cell proliferation and tumor progression of ESCC (36,37).…”

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…Housekeeping mRNAs, for example, cytoskeleton proteins, require a low level of eIF4E, whereas proto-oncogenic and prosurvival proteins such as c-Myc, cyclin D1, Pim-1, survivin, Bcl-2, VEGF have a much higher dependency on eIF4E for translation [11,12]. These mRNAs are termed as 'weak mRNAs' and are greatly influenced by an increase in eIF4E levels, observed in 30% of human cancers [13][14][15]. The availability of eIF4E is regulated by 4E-binding proteins, which compete with eIF4G for a common surface to bind to eIF4E [4,16,17].…”

C-terminal binding protein‑2 mediates cisplatin chemoresistance in esophageal cancer cells via the inhibition of apoptosis

“…DDP is a first-line drug in the treatment for ESCC, and DDP resistance remains a serious challenge. A previous study conducted by the present research team indicated that the expression of CtBP2 was upregulated in ESCC tissues compared with adjacent non-tumorous tissues (17). However, the effect of CtBP2 on the susceptibility of ESCC cells to DDP was unclear.…”

“…Cisplatin (DDP) is a first-line drug in the treatment for ESCC, and the development of DDP resistance in ESCC cells is the main cause of chemotherapy failure (14,15). The effectiveness of chemotherapy depends on the sensitivity of the tumor cells to chemotherapy drugs (16), and ESCC usually exhibits a high resistance to chemotherapy (17,18). Therefore, the identification of oncogenes that may be targeted to combat resistance is likely to be a great benefit to clinical practice.…”