Abstract

Radioresistance is considered as a main factor restricting efficacy of radiotherapy. However, the exact molecular mechanism of radioresistance has not been explained yet. In this study, to elucidate radioresistance mechanism in lung cancer, we compared radiation responses in two types of non-small cell lung cancer (NSCLC) cells with different radiosensitivity and identified key molecules conferring radioresistance. In radioresistant NSCLC cells, ionizing radiation (IR) led to casein kinase 2α (CK2α)- and PKC-mediated phosphorylation of rpS3 and TRAF2, respectively, which induced dissociation of rpS3-TRAF2 complex and NF-κB activation, resulting in significant up-regulation of prosurvival genes (cIAP1, cIAP2, and survivin). Also, dissociated phospho-rpS3 translocated into nucleus and bound with NF-κB complex (p65 and p50), contributing to p65 DNA binding property and specificity. However, in radiosensitive NSCLC cells, IR-mediated rpS3 phosphorylation was not detected due to the absence of CK2α overexpression. Consequently, IR-induced rpS3-TRAF2 complex dissociation, NF-κB activation, and prosurvival gene expression were not presented. Taken together, our findings revealed a novel radioresistance mechanism through functional orchestration of rpS3, TRAF2, and NF-κB in NSCLC cells. Moreover, we provided the first evidence for the function of rpS3 as a new TRAF2-binding protein and demonstrated that phosphorylation of both rpS3 and TRAF2 is a key control point of radioresistance in NSCLC cells. These results suggest that regulation of rpS3 and TRAF2 in combination with radiotherapy could have high pharmacological therapeutic potency for radioresistance of NSCLC.

Highlights

  • Radioresistance is a critical factor restricting efficacy of radiotherapy

  • We demonstrated that ionizing radiation (IR)-dependent phosphorylation of Ribosomal protein S3 (rpS3) and TNFR-associated factor 2 (TRAF2) by casein kinase 2␣ (CK2␣) and protein kinase C (PKC), respectively, plays an important role in survival signal transduction pathway in non-small cell lung cancer (NSCLC) cells

  • IRinduced dissociation of rpS3-TRAF2 complex was not found under treatment of CK2␣-siRNA and PKC␦-siRNA in irradiated A549 cells (Fig. 4I). These results indicate that rpS3-TRAF2 complex is dissociated only if both rpS3 and TRAF2 are phosphorylated by IR-activated CK2␣ and PKC␦, respectively

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Summary

Introduction

Radioresistance is a critical factor restricting efficacy of radiotherapy. Results: Phosphorylation of both rpS3 and TRAF2 induces dissociation of rpS3-TRAF2 complex and influences radioresistance through activation of NF-␬B pathway. In radioresistant NSCLC cells, ionizing radiation (IR) led to casein kinase 2␣ (CK2␣)- and PKC-mediated phosphorylation of rpS3 and TRAF2, respectively, which induced dissociation of rpS3TRAF2 complex and NF-␬B activation, resulting in significant up-regulation of prosurvival genes (cIAP1, cIAP2, and survivin). We provided the first evidence for the function of rpS3 as a new TRAF2-binding protein and demonstrated that phosphorylation of both rpS3 and TRAF2 is a key control point of radioresistance in NSCLC cells. These results suggest that regulation of rpS3 and TRAF2 in combination with radiotherapy could have high pharmacological therapeutic potency for radioresistance of NSCLC

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