Targeting RNA helicases in cancer: The translation trap

Abstract

Cancer cells are reliant on the cellular translational machinery for both global elevation of protein synthesis and the translation of specific mRNAs that promote tumor cell survival. Targeting translational control in cancer is therefore increasingly recognized as a promising therapeutic strategy. In this regard, DEAD/H box RNA helicases are a very interesting group of proteins, with several family members regulating mRNA translation in cancer cells. In this review, we delineate the mechanisms by which DEAD/H box proteins modulate oncogenic translation and how inhibition of these RNA helicases can be exploited for anti-cancer therapeutics.

Keywords: DDX; DDX3; RNA helicase; Translation; eIF4A.

Figure 1. DEAD/H box RNA helicases mediate cap-dependent translation initiation of oncogenic mRNAs with a complex 5′UTR structure

A. Schematic representation of cap-dependent translation. The three subunits of the eIF4F translation initiation complex recruit the 40S ribosomal unit to the 5′ m⁷G-cap mRNA structure and together with several initiation factors and the initiator tRNA form the 43S pre-initiation complex, which scans the 5′UTR until it encounters the AUG start codon. Subsequently, the 60S ribosomal unit is recruited and together with the now 48S small subunit forms the mature 80S ribosomal complex that is competent for translation elongation. Cap-dependent translation is stimulated by oncogenic PI3K/Akt/mTOR signaling through phosphorylation and hereby inactivation of eIF4E-binding protein (4E-BP), which sequesters eIF4E from eIF4F, and via activation of S6K1, which inactivates PCDA, an eIF4A inhibitor. B. Schematic representations of how RNA helicases facilitate cap-dependent translation of mRNAs with a complex 5′UTR region. eIF4A (DDX2) unwinds secondary structures in the 5′UTR and is essential for translation of mRNAs with G-quadruplexes^{44, 45}. DHX29 modifies the 40S ribosomal subunit and hereby enhances its processing activity[25]. DDX3 was found to facilitate both translation of general complex secondary structures[32, 33], as well as mRNAs with secondary structure in immediate vicinity to their m⁷GTP cap[31]. RHA (DHX9) promotes translation of mRNAs with a specific RNA sequence containing two stemloop structures known as the post-transcriptional control element (PCE) in their 5′ UTR[50]. C. Alternative roles for DDX3 as a translational repressor through binding and sequestration of eIF4E have also been reported[29].

Figure 2. Specific DEAD/H box proteins are required for IRES-dependent translation due to oncogenic stress

Schematic representation of how cellular stress conditions that occur frequently in cancer cells inhibit global cap-dependent translation and activate IRES-dependent of selected mRNAs. 40S ribosomes are recruited to the secondary structure of the IRES, either directly or by binding canonical translation initiation factors like eIF3 and eIF4G or specific IRES transacting factors (ITAFs)[25]. Both eIF4A and DDX3 facilitate IRES dependent translation of specific mRNAs[59]^, , whereas the conformational changes imposed by DHX29 on the 40S ribosome, impede ribosomal binding to certain IRES[25].

Figure 3. The involvement of RNA helicases in mitochondrial translation promotes cancer through synthesis of OXPHOS proteins

Schematic representation of how exposure to stressors in the cancer cell environment (e.g., radiotherapy) can cause a sudden increase in the need for ATP, which is met by mitochondrial upregulation of oxidative phosphorylation, hereby supporting cancer cell survival. Oxidative phosphorylation (OXPHOS) occurs on the inner mitochondrial membrane. Complexes I–IV of the electron transport chain create a H⁺-gradient that fuels ATP-synthase (complex V), which converts ADP into ATP. The mitochondrial genome (mtDNA) contains genes encoding 13 proteins that are all part of OXPHOS complexes. Mitochondrial mRNAs (mt-mRNA) are translated by the mitochondrial translation complex called the mitoribosome. Assembly of the 28S small and 39S large mitoribosome subunits occurs in a distinct mitochondrial area called the mitochondriolus[73], and is facilitated by DDX28[73], DHX30[74] and possibly DDX3[48].

Figure 4. Working mechanism of eIF4A inhibitors

Schematic representation of how eIF4A inhibitors affect cap-dependent translation of mRNAs with specific 5′UTR features. Hippurastinol (Hipp) binds to the c-terminal domain of eIF4A and was found to specifically inhibit its ATPase, helicase and mRNA binding activity[19]. Pateamine A (PatA) stimulates RNA binding activity of free eIF4A (eIF4A_F)[79], most likely hereby sequestering it and perturbing the interactions with other translation initiation factors[81]. Of the family of Rocaglates, Rocaglamide A (RocA) clamps eIF4A on mRNAs that have short polypurine sequences in their 5′UTR, hereby putting up a roadblock for ribosomal scanning[78]. Silvestrol, one of the most studied rocaglates is thought to sequester eIF4A from the eIF4F complex by its increased RNA affinity[23, 83], whether it also has a polypurine specificity remains to be determined.