eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling

Abstract

Activation of translation initiation is essential for the malignant phenotype and is emerging as a potential therapeutic target. Translation is regulated by the expression of translation initiation factor 4E (eIF4E) as well as the interaction of eIF4E with eIF4E-binding proteins (e.g., 4E-BP1). Rapamycin inhibits translation initiation by decreasing the phosphorylation of 4E-BP1, increasing eIF4E/4E-BP1 interaction. However, rapamycin also inhibits S6K phosphorylation, leading to feedback loop activation of Akt. We hypothesized that targeting eIF4E directly would inhibit breast cancer cell growth without activating Akt. We showed that eIF4E is ubiquitously expressed in breast cancer cell lines. eIF4E knockdown by small interfering RNA inhibited growth in different breast cancer cell subtypes including triple-negative (estrogen receptor/ progesterone receptor/HER-2 -negative) cancer cells. eIF4E knockdown inhibited the growth of cells with varying total and phosphorylated 4E-BP1 levels and inhibited rapamycin-insensitive as well as rapamycinsensitive cell lines. eIF4E knockdown led to a decrease in expression of cyclin D1, Bcl-2, and Bcl-xL. eIF4E knockdown did not lead to Akt phosphorylation but did decrease 4E-BP1 expression. We conclude that eIF4E is a promising target for breast cancer therapy. eIF4E-targeted therapy may be efficacious in a variety of breast cancer subtypes including triple-negative tumors for which currently there are no targeted therapies. Unlike rapamycin and its analogues, eIF4E knockdown is not associated with Akt activation.

SP600125 Inhibits Cap-dependent Translation Independently of the c-Jun N-terminal Kinase Pathway

“…This observation is similar to the suppression of cap-dependent translation observed at the initiation step (Soni et al, 2008). In agreement, reporter analysis using exogenous mRNA clearly indicates that SP inhibits cap-dependent translation but not IRES-dependent translation.…”

“…The areas corresponding to polysome decreased to approximately 72% (J774.1 cells) and approximately 71% (Swiss 3T3 cells) by the SP treatment. Since similar changes of polysomal and non-polysomal peaks have been observed in the cells defective in translational initiation (Soni et al, 2008), SP is likely to inhibit translational initiation.…”

MYC directs transcription of MCL1 and eIF4E genes to control sensitivity of gastric cancer cells toward HDAC inhibitors

“…This BCL XL expression. 48 The observation that SAHA doses above the IC 50 value regulate BCL XL expression in the cellular models investigated, without changing eIF4E expression, argues that HDACi control BCL XL beyond the c-MYC-eIF4E axis.…”

Translational control of cell fate: From integration of environmental signals to breaching anticancer defense

“…This effect is mediated by the ability of eIF4F to block Myc-induced apoptosis 90,91 through translational activation of negative regulators of the apoptotic machinery, such as Bcl-X L . [92][93][94] Along with this, enforced expression of 4E-BP1 sensitizes Ras-transformed cells to drug-induced apoptosis in a manner dependent on the ability of 4E-BP1 to sequester eIF4E. 92,95 Survival signals from serum growth factors 90 and interleukin-6, 96 operate through the PI3K/Akt/mTORC1/ eIF4E cascade to suppress the innate apoptotic machinery.…”