Translational Control in Cancer

A long-standing interest in our lab has been in investigating the role of translational control in cancer. In our seminal 1990 Nature paper, we reported that the overexpression of the cap-binding protein, eIF4E, would disrupt the competition set-up among mRNAs for ribosomes, leading to malignant transformation of rodent fibroblasts. Since then, we have demonstrated that over- expression of eIF4E in mouse cancer models accelerates tumorigenesis. Furthermore, eIF4E is over-expressed in many human cancers and has been proposed as an independent prognostic tumour marker in breast cancer.

In another landmark paper (Nature, 1994), we described the cloning of cDNAs encoding eIF4E-binding proteins (4E-BPs), which interacts with eIF4E to regulate protein synthesis upon insulin simulation. In 1996, our work in The EMBO Journal demonstrated that rapamycin blocks cap-dependent translation in cells while leaving the cap-independent translation intact.

This observation led to the discovery that the mTOR (mammalian Target of Rapamycin) kinase pathway regulates translation by phosphorylating 4E-BPs and thus controlling the availability of eIF4E to assemble into the eIF4F complex. In a more recent seminal paper in Science (2010), we showed that downstream of mTORC1, 4E-BPs control proliferation, while S6 kinases (another important substrate of mTOR) control cell growth. 

We postulated that 4E-BPs might act as tumour suppressor as they antagonize eIF4E activity. Indeed, we showed that the over-expression of 4E-BP1 in eIF4E-transformed cells reverses their tumorigenicity. We bolstered the tumour-suppressor activity of 4E-BPs using 4E-BPs ‘knock-out’ mice, suggesting that the inhibitors of eIF4F activity should act as potential novel anti-cancer drugs. Following our work, several pharmaceuticals have targeted eIF4E, with a prominent work which lead to a clinical trial by the Eli Lilly Co., showing that the anti-sense eIF4E inhibits tumour growth (NCT00903708).

Selected Papers:

  1. Nathaniel Robichaud, Brian E Hsu, Roman Istomine, Fernando Alvarez, Julianna Blagih, Eric H Ma, Sebastian V Morales, David L Dai, Glenn Li, Margarita Souleimanova, Qianyu Guo, Sonia V Del Rincon, Wilson H Miller Jr, Santiago Ramón Y Cajal, Morag Park, Russell G Jones, Ciriaco A Piccirillo, Peter M Siegel, Nahum Sonenberg (2018). Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils. PNAS. doi: 10.1073/pnas.171743911

  2. Luc Furic, Liwei Rong, Ola Larsson, Nahum Sonenberg (2010). eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. PNAS. doi: 10.1073/pnas.100532010

  3. Ryan J O Dowling, Ivan Topisirovic, Tommy Alain, Michael Bidinosti, Bruno D Fonseca, Emmanuel Petroulakis, Xiaoshan Wang, Ola Larsson, Anand Selvaraj, Yi Liu, Sara C Kozma, George Thomas, Nahum Sonenberg (2010). mTORC1-mediated cell proliferation but not cell growth, controlled by the 4E-BPs. Science. doi: 10.1126/science.1187532

  4. Anthoula Lazaris-Karatzas, Kathleen S. Montine, Nahum Sonenberg (1990). Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature. doi: 10.1038/345544a0