Radioresistant cervical cancer shows upregulation of the NHEJ proteins DNA-PKcs, Ku70 and Ku86

Abstract

BACKGROUND: Radiotherapy is central in the treatment of cervical cancer. The formation of DNA double-strand breaks is considered to be critical for the radiotherapeutic effect. The non-homologous end joining (NHEJ) proteins DNA -PKcs, Ku70 and Ku86 have a major role in repairing DNA lesions. The objective of this study was to analyse if the expression of DNA -PKcs, Ku70 and Ku86 and their downstream signalling molecules p53, p21 and Mdm-2 are altered in residual cervical tumours after radiotherapy. METHODS: Retrospective analysis of 127 patients with cervical cancer stage IB-IIA treated with preoperative radiotherapy and radical surgery, revealed residual tumour in the cervical specimen in 30 patients. In 22 cases tumour material from residual and corresponding primary tumour were retrieved and the expression of DNA -PKcs, Ku86, Ku70, p53, p21 and Mdm-2 were assessed by immunohistochemistry. RESULTS: Residual tumours showed increased frequency of DNA -PKcs (P ¼ 0.037), Ku70 (P ¼ 0.018), Ku86 (P ¼ 0.008) positive cells. A correlation in DNA -PKcs expression between primary and residual tumours was found. The frequency of p21-positive cells was decreased (P ¼ 0.007) in residual tumours whereas no change in p53 or Mdm-2-positive cells were observed. CONCLUSION: Our results show that cervical carcinoma surviving radiotherapy have an increased DNA -PK expression. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of DNA -PK function may be part of a radioresistance mechanism within this tumour type.

Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells

“…Accordingly, DNA-PK-deficient cells have ineffective DSB repair and are exquisitely sensitive to DSB-inducing agents (4). Conversely, upregulation of DNA-PK promotes repair of DSBs leading to tumor radioresistance preclinically (5) and clinically (6)(7)(8). Thus, DNA-PK is an important molecular target for inhibiting DSB repair and enhancing the cytotoxicity of radiation.…”

MicroRNAs and Their Impact on Radiotherapy for Cancer

“…Despite increasing knowledge about the effects of radiation on biochemical pathways, the exact mechanisms of intrinsic radioresistance remain unclear. To date, it has been reported that a number of key cellular features appear to play a role in the development of intrinsic radioresistance, including overexpression of DNA repair proteins (8), modifications of signaling pathways (9), angiogenesis (10) and the presence of cancer stem cells (11).…”

High Expression of SOX2 and OCT4 Indicates Radiation Resistance and an Independent Negative Prognosis in Cervical Squamous Cell Carcinoma

“…Radiosensitivity can be influenced by both intrinsic and extrinsic factors such as hypoxia (Rockwell et al 2009; 532654J HCXXX10.1369/0022155414532654Shen et alCorrelation of SOX2 and OCT4 with Radiation Resistance research-article2014 Dewhirst et al 2008), the cell cycle (Shimura et al 2010;He et al 2011), DNA damage and repair (Bolderson et al 2009;Beskow et al 2009), apoptosis (Lehmann et al 2007;Suzuki et al 2007), growth factors and oncogenes (Mukherjee et al 2009;Bergkvist et al 2011), cancer stem cells (CSCs) and the epigenetic modification of genes (Baumann et al 2008;Kawano et al 2010). CSCs, which have been recognized as a source of local or distant cancer relapse, have the potential to dramatically affect clinical outcomes (Brunner et al 2012).…”