Meta-analysis of the prognostic value of p-4EBP1 in human malignancies

Abstract

Phosphorylated 4E-binding protein 1 (p-4EBP1) is the inactivated form of 4EBP1, which is a downstream mediator in the mTOR signaling pathway and a vital factor in the synthesis of some oncogenic proteins. This meta-analysis was conducted to assess the predicative value of p-4EBP1 expression in human malignancies. The PubMed and Embase databases were carefully searched. Articles comparing the prognostic worthiness of different p-4EBP1 levels in human malignancies were collected for pooled analyses and methodologically appraised using the Newcastle-Ottawa Scale (NOS). A total of 39 retrospective cohorts with an overall sample size of 3,980 were selected. Patients with lower p-4EBP1 expression had better 3-year (P < 0.00001), 5-year (P < 0.00001), and 10-year (P = 0.03) overall survival and better 3-year (P < 0.0001) and 5-year (P = 0.0005) disease-free survival. Subgroup analyses confirmed the unfavorable prognosis associated with p-4EBP1 overexpression. These findings were further validated by sensitivity analyses. Harbord and Peters tests revealed no publication bias within the included studies. It thus appears higher expression of p-4EBP1 indicates a poor prognosis in human malignancies.

Transcription Factor EB regulates phosphatidylinositol-3-phosphate levels on endomembranes and alters lysosome positioning in the bladder cancer model

“…Thus, the preferential phosphorylation of 4EBP1 in high-grade cancer cell lines could allow to simultaneously keep maintenance of the cellular translation machinery and the nuclear translocation of TFEB that both seem to be regulated mutually exclusive by mTORC1 in non-transformed cells (Perera et al 2016). Given the fact that 4EBP1 has been suggested to be a tumor suppressor and its overexpression was shown to be associated with an unfavorable prognosis in a recent meta-analysis (Zhang et al, 2017), including bladder cancer, our results suggest that shifting substrates could be a strategy to fuel the overgrowth of bladder cancers. In the future, it will be important to further investigate whether this mechanism could be a driving progress in bladder cancer and potentially other cancer models.…”

Small Molecule Activators of B56-PP2A Restore 4E-BP Expression and Function to Suppress Cap-dependent Translation in Cancer Cells

“…1A) and protein (Fig. 1B); however, loss of 4E-BP1 function is achieved in these tumors by inhibitory phosphorylation downstream of oncogenic kinases such as mTOR and ERK (39)(40)(41)(42). Thus, expression of high levels of inactive, hyperphosphorylated 4E-BP1 is a characteristic of many cancers.…”

Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

“…4E-BP1 is hyperphosphorylated by mTORC1, inhibiting its binding to eukaryotic initiation factor 4E (eIF4E), leading to cap-dependent translation of key cell cycle regulators such as MYC or CYCLIN D1 [32]. 4E-BP1 is known to inhibit mRNA translation in healthy cells; however, it has been seen to be overexpressed in numerous human cancers and has been linked with a poor prognosis in numerous cases [33][34][35]. S6K1 (p70S6Kα) or p70S6 kinase is also phosphorylated by mTORC1, which results in the downstream phosphorylation of S6 ribosomal protein (rpS6) [36].…”