Effect of eIF3a on Response of Lung Cancer Patients to Platinum-Based Chemotherapy by Regulating DNA Repair

Abstract

Purpose: The purpose of this study is to test the hypothesis that eIF3a may regulate the expression of DNA repair proteins which, in turn, affects response of lung cancer patients to treatments by DNAdamaging anticancer drugs.Experimental Design: Immunohistochemistry was used to determine the expression of eIF3a in 211 human lung cancer tissues followed by association analysis of eIF3a expression with patient's response to platinum-based chemotherapy. Ectopic overexpression and RNA interference knockdown of eIF3a were carried out in NIH3T3 and H1299 cell lines, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin, doxorubicine, etoposide (VP-16), vincristine, and vinblastine by using MTT assay. The DNA repair capacity of these cells was evaluated by using host-cell reactivation assay. Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of eIF3a on the DNA repair genes by using cells with altered eIF3a expression.Results: eIF3a expression associates with response of lung cancer patients to platinum-based chemotherapy. eIF3a knockdown or overexpression, respectively, increased and decreased the cellular resistance to cisplatin and anthrocycline anticancer drugs, DNA repair activity, and expression of DNA repair proteins.Conclusions: eIF3a plays an important role in regulating the expression of DNA repair proteins which, in turn, contributes to cellular response to DNA-damaging anticancer drugs and patients' response to platinum-based chemotherapy. Clin Cancer Res; 17(13); 4 -9. Ó2011 AACR.

Downregulation of RIF1 Enhances Sensitivity to Platinum-Based Chemotherapy in Epithelial Ovarian Cancer (EOC) by Regulating Nucleotide Excision Repair (NER) Pathway

“…XPA level was also related to platinum resistance in non-small cell lung cancer [51]. The increased expression level of RPA70 and RPA32 reduced chemosensitivity of lung cancer cells to cisplatin, while decreased expression level of these proteins enhanced chemosensitivity [12]. Our results are consistent with the previous reported studies.…”

Spectrin Domain of Eukaryotic Initiation Factor 3a Is the Docking Site for Formation of the a:b:i:g Subcomplex

“…These conserved residues, similar to Phe 760 , could be essential in contributing to the binding by eIF3i. These findings implicate that specific residues such as Phe 760 may be used as a target for identification of compounds that can inhibit eIF3a binding to eIF3b without affecting the binding to eIF3i or vice versa to dissect the translational control of specific mRNAs (8,(21)(22)(23) and for development of potential therapeutics. The latter is particularly interesting as eIF3a overexpression has been found in various human cancers (7, 24 -26), and eIF3a overexpression may be oncogenic (20,27).…”

The role of eIF3 and its individual subunits in cancer

“…Most interesting are reports that the level of 3a in cells affects the translation of specific mRNAs; high 3a stimulates the synthesis of tyrosinated α-tubulin, the ribonucleotide reductase regulator M2 and the N-myc downstream regulated gene-1 (NDRG1), and inhibits p27kip1 synthesis, whereas low 3a produces the reverse outcomes [80,82,83]. Similar effects on other mRNAs may be responsible for regulating cisplatin sensitivity and DNA repair activities [84,85]. A strong correlation between 3a and p27kip1 levels is seen in non-small cell lung cancers [77,86].…”