Retracted Article: Down-regulation of the radiation-induced pEGFR^Thr654 mediated activation of DNA-PK by Cetuximab in cervical cancer cells

Abstract

The phosphorylation of EGFR Thr654 is required for nuclear EGFR importing, and our previous study has shown that pEGFR Thr654 is an independent prognostic factor for the low survival rate of patients with cervical squamous carcinoma. Now, we aim to examine the role of pEGFR Thr654 in the activation of DNA-PK and radio resistance. Either CaSki or HeLa cells were exposed to a dose of 4 Gy with a 6 MV Xray in the presence or absence of Cetuximab or Gefitinib, then EGFR, pEGFR Thr654 , DNA-PKcs and pDNA-PK Thr2609 levels were determined using a western blot. DNA damage was quantified with gH2AX foci analysis and the response of CaSki and HeLa cells to irradiation was determined using a colony formation assay. In CaSki and HeLa cells, irradiation induced nuclear EGFR accumulation, and pEGFR Thr654 and pDNA-PK Thr2609 levels were both significantly increased. Cetuximab pre-treatment significantly reduced the expression of pEGFR Thr654 and pDNA-PK Thr2609 and enhanced the gH2AX foci per cell and sensitivity enhancement ratio in CaSki cells. Gefitinib pre-treatment had a similar but weaker effect. In HeLa cells, similar effects of Cetuximab and Gefitinib on pEGFR Thr654 and pDNA-PK Thr2609 were observed, and no significant difference was found. We found that Cetuximab had a better effect than Gefitinib on attenuating the radio resistance in cervical squamous carcinoma cells via inhibiting pEGFR Thr654 -mediated nuclear EGFR transport and related DNA-PK T2609 -mediated DNA repair. However, in adenocarcinoma cells, both EGFR-targeted drugs had no remarkable effects on the radio sensitivity.Taken together, radiotherapy combined with Cetuximab may be a promising strategy to improve the therapeutic gain for cervical squamous carcinoma patients.

A disulfide-induced supra-amphiphilic co-assembly for glycosylated pro-drug-photosensitizer nanoparticles in combination therapies

“…In addition, we speculate that, due to the low expression of galectins on the surface of HeLa cells, 32 the uptake of BG-L NPs by HeLa cells may be partly due to the interaction between Gef and highly expressed EGFR on the cell membrane of HeLa. 33 The biocompatibility and cytotoxicity of BG-L NPs were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 24 For HL7702 cells, after incubation with different concentrations of BG-L NPs (0-20 mM) for 48 h, the cell viability in BG-L NP treated groups was higher than that in the Gef group (Fig.…”

“…In addition, we speculate that, due to the low expression of galectins on the surface of HeLa cells, 32 the uptake of BG-L NPs by HeLa cells may be partly due to the interaction between Gef and highly expressed EGFR on the cell membrane of HeLa. 33…”

Exploiting DNA repair pathways for tumor sensitization, mitigation of resistance, and normal tissue protection in radiotherapy

“…These results suggest that tumor EGFR status can be used to personalize radiotherapy treatment plans and augmentation with NHEJ inhibitors. The link between EGFR and DSB repair suggests strategies to modulate tumor radiosensitivity by inhibiting NHEJ indirectly with available drugs that target EGFR and AKT1/3 pathways [148,160] .…”