Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation

Abstract

Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation. Among a series of 23 natural compounds evaluated, silvestrol, which inhibits eIF4A, was identified as being the most growth inhibitory in both primary meningioma and Ben-Men-1 cells. Silvestrol treatment of meningioma cells prominently induced G2/M arrest. Consistently, silvestrol significantly decreased the amounts of cyclins D1, E1, A, and B, PCNA and Aurora A. In addition, total and phosphorylated AKT, ERK and FAK, which have been shown to be important drivers for meningioma cell proliferation, were markedly lower in silvestrol-treated Ben-Men-1 cells. Our findings suggest that inhibiting protein translation could be a potential treatment for meningiomas.

PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance

“…PDCD4 may regulate cell-cycle progression by inhibiting eIF4A, an RNA helicase and translation initiation factor. PDCD4 knockdown induced the expression of c-Myc and Cyclin E1, two eIF4A-regulated transcripts associated with cell-cycle progression (28,29), in LNCaP-shPDCD4 cells, but not LAPC4-shPDCD4 cells ( Supplementary Fig. S5C).…”

Update on Phytochemical and Biological Studies on Rocaglate Derivatives from Aglaia Species

“…The inhibition of the overexpressed eIF4F components in meningiomas was also investigated using a panel of 23 natural products, inclusive of representatives of the cucurbitacin, diarylheptanoid, rocaglate, simaroubolide, stilbenoid, sesquiterpene lactone, and xanthone structural classes [65]. Of the compounds examined, silvestrol (8) and episilvestrol (9) were the 2 most growth-inhibitory compounds, with silvestrol being more potent (IC 50 10 nM) than episilvestrol (IC 50 32 nM) against NF2-deficient meningioma Ben-Men-1 cells.…”

Translating from cancer to the brain: regulation of protein synthesis by eIF4F

“…Much of the research centered on eIF4F, including details of how the complex assembles and what individual components do, was first studied in cancer cell lines (see Pelletier et al 2015 for an excellent review that focuses on the role of eIF4F in cancer). The eIF4F factors, particularly eIF4E, have been shown to be up-regulated in a variety of cancers and cancer cell lines from lymphomas to breast cancer, which is thought to increase the translation of other procancer proteins (Kerekatte et al 1995;Miyagi et al 1995;Anthony et al 1996;Rosenwald et al 1999;Wang et al 1999;Bauer et al 2001Bauer et al , 2002Seki et al 2002;De Benedetti and Graff 2004;Ruggero et al 2004;Lin and Aplan 2007;Wendel et al 2007;Horvilleur et al 2014;Modelska et al 2015;Jaiswal et al 2018;Oblinger et al 2018;Wen et al 2007). Conversely, targeting eIF4F factors in cancer has been shown to decrease the translation of cancer-relevant proteins, decrease tumor growth, and/or make cancer cells more susceptible to cell death, with promising preclinical results.…”