Targeting mTOR and eIF4E: a feasible scenario in ovarian cancer therapy

Abstract

Ovarian carcinoma is one of the most common causes for cancer death in women; lack of early diagnosis and acquired resistance to platinum-based chemotherapy account for its poor prognosis and high mortality rate. As with other cancer types, ovarian cancer is characterized by dysregulated signaling pathways and protein synthesis, which together contribute to rapid cellular growth and invasiveness. The mechanistic/mammalian target of rapamycin (mTOR) pathway represents the core of different signaling pathways regulating a number of essential steps in the cell, among which protein synthesis and the eukaryotic initiation factor 4E (eIF4E), the mRNA cap binding protein, is one of its downstream effectors. eIF4E is a limiting factor in translation initiation and its overexpression is a hallmark in many cancers. Because its action is regulated by a number of factors that compete for the same binding site, eIF4E is an ideal target for developing novel antineoplastic drugs. Several inhibitors targeting the mTOR signaling pathway have been designed thus far, however most of these molecules show poor stability and high toxicity in vivo. This minireview explores the possibility of targeting mTOR and eIF4E proteins, thus impacting on translation initiation in ovarian cancer, describing the most promising experimental strategies and specific inhibitors that have been shown to have an effect on other kinds of cancers.

Keywords: Ovarian cancer; eIF4E; inhibitors; mTOR pathway; targeted therapy.

Figure 1

PI3K/mTOR pathway and regulation of eIF4F complex. (A) PI3K and its downstream effectors AKT and mTOR are activated by many extracellular stimuli. The serine/threonine protein kinase mTOR forms, by association with several binding partners (mLST8, Raptor/Rictor, and mSIN1), 2 distinct complexes mTORC1 and mTORC2. mTORC2 activation leads to actin regulation and cytoskeleton organization, while mTORC1 allows the cap-dependent translation through the 4E-BPs phosphorylation, resulting in the dissociation of these proteins from eIF4E. PI3K pathway dysregulation results in an altered proliferation, carcinogenesis, and angiogenesis. (B) The cap-binding protein eIF4E is released by 4E-BPs as a result of its phosphorylation by mTORC1, allowing eIF4F complex formation and thus permitting translation of eIF4E-sensitive mRNAs.