Downregulation of eukaryotic initiation factor 4A1 improves radiosensitivity by delaying DNA double strand break repair in cervical cancer

Abstract

Abstract. Expression of eukaryotic initiation factor 4A1 (eIF4A1) following brachytherapy has been reported to predict improved radiosensitivity and tumor-specific survival in cervical cancer. Therefore, the present study investigated the function of eIF4A1 in cervical cancer and the mechanism by which eIF4A1 regulates cervical cancer radiosensitivity. It was determined that the downregulation of eIF4A1 in HeLa and SiHa cells notably attenuated cell proliferation, in addition to repressing cervical cancer migration and invasion, and promoting cell apoptosis. In vitro and in vivo studies have demonstrated that silencing eIF4A1 improves cervical cancer radiosensitivity. Detection of γ-H2AX using western blot analysis at 0, 0.5, 1, 6 and 24 h following the exposure of cervical cancer cells to X-rays illustrated that eIF4A1-knockdown results in postponed radiation-induced DNA double strand break (DSB) repair. Overall, the results of the present study demonstrated that downregulated eIF4A1 improves cervical cancer radiosensitivity by delaying cancer cell DSB repair. In conclusion, the data indicated that eIF4A1 performs a vital role in cervical cancer progression and radiosensitivity. Therefore, eIF4A1 may be a potential therapeutic target in patients with cervical cancer. IntroductionAlthough the incidence of cervical cancer has decreased due to more regular cytological screening programs and the success of human papillomavirus vaccinations, it remains the third most common type of gynecological cancer worldwide (1).The International Agency for Research on Cancer estimated there were 528,000 new cases and 266,000 deaths in 2012, and a total of ~9/10 (87%) of cervical cancer mortalities occur in less developed regions (2). At present, radiotherapy, as an adjuvant or primary treatment, remains the most common and effective therapeutic intervention for cervical cancer. Several international clinical trials have reported that adjuvant radiotherapy or concurrent chemoradiation therapy can improve disease-free survival and overall survival outcomes in patients with pathological risk factors for recurrence (3-5). However, radiotherapy ultimately fails in >20% of patients with locally advanced cervical cancer (FIGO stage IB2-IVA), the main cause of which is radio-resistance (6,7). Clinically, the identification and treatment of radio-resistant cervical cancer remains a challenge.Eukaryotic initiation factor (eIF) 4F is composed of ATP-dependent RNA helicase eIF4A1, 5' cap mRNA-binding protein eIF4E and the scaffolding protein eIF4G, which scans mRNAs through the 5' untranslated region (5'UTR), and unwinds the mRNA secondary structure to expose the translation initiation codon and initiates translation (8,9). Assembly of the eIF4F complex is rate-limiting step for translation initiation. Increased eIF4F complex formation elevates the translation of all cap-dependent mRNAs, thereby increasing global protein synthesis rates. However, mRNAs vary widely in their inherent translatability, largely as a function of differences in t...

The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage

“…Among these control condition interacting proteins, we found several that were strongly associated with DNA stability management, e.g . EIF4A1 [60], RPS27A [61], MAP4 [62] and PHB [63]. Upon the introduction of the two age-related perturbagens, H 2 O 2 and CPT, we found a profound increase – potentially due to a functional stabilization of the interactome complexes [64] – in the size of the stress-associated RXFP3 interactomes (Figure 5A).…”

The eIF4A inhibitor silvestrol sensitizes T-47D ductal breast carcinoma cells to external-beam radiotherapy

“…In a previous study on cervical cancer, the double strand break (DSB) marker γ-H2AX became elevated 30 min after irradiation with 10 Gy, reducing significantly after six hours [15] . This reduction in γ-H2AX was not seen in cells treated with shRNAs targeting eIF4AI [15] . This highlights the potential involvement of eIF4A in the post-irradiation DNA damage response.…”

Value of Diffusion-Weighted Magnetic Resonance Imaging Combined with miR-18a Level in Predicting Radiosensitivity of Cervical Cancer

“…Some reports indicated that miR-18a can increase cellular radiosensitivity of cervical cancer. Overexpression of miR-18a suppressed the level of ataxia-telangiectasia mutated (ATM) and attenuated DNA double-strand break (DSB) repair, which re-sensitized the cervical cancer cells to radiotherapy by promoting apoptosis [ 10 , 25 ]. In our research, we found that higher expression of miR-18a in cervical cancer cells resulted in more radiosensitivity.…”

“…MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs that play critical roles in tumor proliferation, progression, and metastasis [ 10 ]. Previous studies have revealed that many miRNAs participate in biological responses of cervical cancer, and miR-18a, miR-132, and miR-145 have been reported to modulate the radiosensitivity of cervical cancer cells [ 11 – 13 ].…”