eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA.

Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (−) and the eIF4A-inhibitor Silvestrol

“…So far, no published data on the pharmacokinetic properties of CR-31-B (−) are available. It was already shown that daily intraperitoneal injection of CR-31-B (−) works well in mice (Wolfe et al, 2014;Chan et al, 2019) while the systemic availability of rocaglates following oral application seems to be limited (Saradhi et al, 2011). Based on this and our own data, we conclude that CR-31-B (−) may represent an interesting alternative to the broad-spectrum antiviral Silvestrol, which remains to be confirmed in appropriate in vivo studies to evaluate and compare the antiviral potential, toxicity and pharmacokinetics profiles of the two compounds.…”

High expression of eIF4A2 is associated with a poor prognosis in esophageal squamous cell carcinoma

“…For example, the upregulation of eIF4E functions as an effective indicator for ~30% of all cancer cases tested, and the phosphorylation of eIF4E promotes cellular proliferation and inhibits apoptosis (12). eIF4A2 was the focus of the present study, and is a subunit of eIF4A that is associated with the oncogenic translation of PDA (24). eIF4A is a subunit of eIF4F that also comprises eIF4E (a cap binding protein) and eIF4G (a regulatory scaffold protein).…”

“…Biologically identified as an ATP-dependent RNA helicase, eIF4A2 belongs to the eukaryotic initiation factor (eIF) family, which is essential for translation initiation (30). Existing findings have established various associations between the eIFs and carcinogenesis, as well as patient prognosis (11,13,24). For example, the upregulation of eIF4E functions as an effective indicator for ~30% of all cancer cases tested, and the phosphorylation of eIF4E promotes cellular proliferation and inhibits apoptosis (12).…”

“…However, recent studies have reported that unlike eIF4A1, eIF4A2 interacts with the CCR4-NOT transcription complex and is involved in the inhibition of miRNA-mediated translation (18). As such, the upregulation of eIF4A1 is reportedly associated with a diverse range of malignancies, including non-small cell lung cancer (NSCLC), endometrial carcinoma, cervical cancer, breast cancer, malignant peripheral nerve sheath tumors and pancreatic ductal adenocarcinoma (PDA) (19)(20)(21)(22)(23)(24). Several relevant studies have also demonstrated that the expression of eIF4A2 is positively correlated with the prognosis of NSCLC and breast cancer (25,26).…”

Revisiting the Concept of Stress in the Prognosis of Solid Tumors: A Role for Stress Granules Proteins?

“…However, we noticed that all SGs nucleators (TIA-1, TIAR, G3BP1, G3BP2, and CAPRIN-1) have an “enhancing” effect on cancer development properties [ 62 , 64 , 65 , 66 , 67 , 68 , 71 , 72 , 73 ], whereas USP10, a SGs inhibitor, has anti-cancer properties [ 74 , 75 ] ( Figure 5 ). There are some interesting correlation between other SGs markers and development, such as eIF3s and eIF4s subunits and complexes, UBAP2L or YB1, for example [ 138 , 155 , 156 , 157 , 158 , 159 , 160 ]. All of those proteins have, in common, to be recruited to SGs or to have role in their regulation [ 31 , 138 , 161 , 162 ].…”