Overexpression of p-4EBP1 associates with p-eIF4E and predicts poor prognosis for non-small cell lung cancer patients with resection

Abstract

Eukaryotic initiation factor 4E (eIF4E) and its phosphorylated form (p-eIF4E) play a crucial role in the protein synthesis, both are under regulation of eIF4E-binding protein 1 (4EBP1) and mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs). This study aims to explore the potential prognostic significance of p-4EBP1 and p-eIF4E in NSCLC patients. The expression of p-4EBP1 and p-eIF4E in NSCLC patients was detected by immunohistochemistry (IHC) staining in tissue microarrays (TMAs) containing 354 NSCLC and 53 non-cancerous lung tissues (Non-CLT). The overexpression percentage of p-4EBP1 and p-eIF4E in lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC) was significantly higher than that of Non-CLT. P-4EBP1 expression in patients with advanced clinical stage was higher than that in early stage. Expression of p-4EBP1 had a positive relationship with p-eIF4E expression both in lung SCC and ADC. NSCLC patients with high expression of p-4EBP1 and p-eIF4E alone or in combination had a lower survival rate than that of other phenotypes. For NSCLC patients, p-4EBP1 is an independent poor prognostic factor as well as clinical stage, LNM and pathological grade. Overexpression of p-4EBP1 and p-eIF4E might be novel prognostic marker for NSCLC, who possesses potential application value for NSCLC targeted therapy.

High EIF4EBP1 expression reflects mTOR pathway activity and cancer cell proliferation and is a biomarker for poor breast cancer prognosis

“…Particularly in response to mTOR-mediated signaling, 4E-BP1 becomes phosphorylated, releasing 4E for subsequent function [21]. In multiple cancer sites, including adrenocortical carcinoma, bladder urothelial, breast, ovarian, endometrial, renal, lung, mesothelioma, hepatocellular and acute myeloid leukemia, phosphorylated 4E-BP1 correlates to poor patient outcomes [45][46][47][48]. However, notability for gastric adenocarcinomas, phosphorylated 4E-BP1 is known to be highly expressed in early rather than late stage cancers, and is correlated with both prolonged disease-free and overall survival [48,49].…”

Targeted Degradation of CDK9 Potently Disrupts the MYC Transcriptional Network

“…This reduction in phosphorylation at specific residues, including Threonine-37/Threonine-46, is known to favor the interaction between 4EBP1 and eIF4E, a factor that is essential for the recruitment of the 40s ribosomal subunits to the 5' end of mRNA 48 . Thus, 4EBP1 binding to eIF4E induces an inhibitory effect on translation 28,48,49 . Taken together, these results demonstrate that KI-CDK9d-32 mediated depletion of CDK9 and MYC levels leads to a robust disruption of MYC regulated processes.…”

Newly Synthesized Anticancer Purine Derivatives Inhibiting p-EIF4E Using Surface-Modified Lipid Nanovesicles

“…The availability of eIF4E is tightly controlled under typical physiological circumstances . eIF4E-binding protein 1 (4EBP1) is the primary regulator of eIF4E availability and a substrate of the mechanistic target of the rapamycin (mTOR) signaling pathway. − To prevent the formation of the translation initiation complex in the dephosphorylated state, 4EBP1 and eIF4G compete for eIF4E’s binding (Figure ). When eIF4E is phosphorylated by upstream signals, primarily mTOR complex 1 (mTORC1), it is released and triggers the synthesis of several proteins, including oncogenic proteins. , However, a recently characterized downstream pathway of MAP kinase-activated protein kinase (MAPKAPK) was also shown to phosphorylate eIF4E on Ser209 via phosphorylation of Mnk1/2 activated by Erk1, Erk2, and p38 MAP kinases released by MAPK .…”

“… 7 eIF4E-binding protein 1 (4EBP1) is the primary regulator of eIF4E availability and a substrate of the mechanistic target of the rapamycin (mTOR) signaling pathway. 8 − 11 To prevent the formation of the translation initiation complex in the dephosphorylated state, 4EBP1 and eIF4G compete for eIF4E’s binding ( Figure 1 ). When eIF4E is phosphorylated by upstream signals, primarily mTOR complex 1 (mTORC1), it is released and triggers the synthesis of several proteins, including oncogenic proteins.…”