Abstract
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 DNA-damaging anticancer drugs. 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. 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. 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.
Highlights
Lung cancer is the most prevalent cancer worldwide and the 5-year survival rate is approximately 16% [1]
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
We show that eIF3a, a translation initiation factor, plays a critical role in regulating the expression of DNA repair proteins which, in turn, may contribute to response of lung cancer to platinumbased chemotherapy. eIF3a, may represent a new prognostic marker predicting drug response and a novel potential target for sensitizing lung cancer to DNA-damaging anticancer drugs in combinational chemotherapy
Summary
Lung cancer is the most prevalent cancer worldwide and the 5-year survival rate is approximately 16% [1]. Major problems in improving survival rate of lung cancer patients is the existence of drug resistance in chemotherapy. There are several known DNA repair pathways [8], DNA damages induced by platinum anticancer drugs is primarily repaired by nucleotide excision repair (NER) mechanism [9]. The increased expression level of these NER proteins has been associated with cisplatin resistance [9,10,11,12,13,14,15]. The underling mechanism for their increased expression in cisplatin-resistant cancers is not yet understood
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