Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

Shimura, Tsutomu; Kakuda, Satoshi; Ochiai, Yoshihiro; Nakagawa, Hiroshi; Kuwahara, Yoshikazu; Takai, Yoshihiro; Kobayashi, Junya; Komatsu, Kenshi; Fukumoto, Manabu

doi:10.1038/onc.2010.238

Cited by 123 publications

(155 citation statements)

References 45 publications

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“…Previous studies revealed that elevated levels of cyclin D1 confer radiation resistance of cancer cells (29,30) and high levels of cyclin D1 correlate with unfavorable response to radiotherapy (31,32). Conversely, suppression of cyclin D1 sensitizes cancer cells to DNA damage (29,33).…”

Section: P16ink4a Inhibits Recruitment Of Rad51 To the Sites Of Dna Dmentioning

confidence: 99%

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

et al. 2014

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The p16INK4a protein is a principal cyclin-dependent kinase inhibitor that decelerates the cell cycle. Abnormally high levels of p16INK4a are commonly observed in human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC). We and others found that p16INK4a overexpression is associated with improved therapy response and survival of patients with HNSCC treated with radiotherapy. However, the functional role of p16INK4a in HNSCC remains unexplored. Our results implicate p16INK4a in regulation of homologous recombination-mediated DNA damage response independently from its role in control of the cell cycle. We found that expression of p16INK4a dramatically affects radiation sensitivity of HNSCC cells. p16INK4a overexpression impairs the recruitment of RAD51 to the site of DNA damage in HPV-positive cells by downregulating of cyclin D1 protein expression. Consistent with the in vitro findings, immunostaining of HNSCC patient samples revealed that high levels p16INK4a expression significantly correlated with decreased cyclin D1 expression. In summary, these findings reveal an unexpected function of p16INK4a in homologous recombination-mediated DNA repair response and imply p16INK4a status as an independent marker to predict response of patients with HNSCC to radiotherapy. Cancer Res; 74(6);

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Section: P16ink4a Inhibits Recruitment Of Rad51 To the Sites Of Dna Dmentioning

confidence: 99%

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

et al. 2014

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Shen

Huang

Xie

et al. 2014

J Histochem Cytochem.

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SummaryRadiotherapy (RT) as a preoperative or postoperative adjuvant or primary treatment is the most common management modality for locally advanced cervical cancer. Radioresistance of tumor cells remains a major therapeutic problem. Consequently, we aimed to explore if the stem cell biomarkers SOX2 and OCT4 protein could be used to predict radioresistance in patients with locally advanced cervical squamous cell carcinoma (LACSCC). These 132 patients were divided into two groups (radiation-resistant and radiation-sensitive groups) according to progress-free survival (PFS). Using pretreatment paraffin-embedded tissues, we evaluated SOX2 and OCT4 expression using immunohistochemical staining. The percentage of overexpression of SOX2 and OCT4 in the radiation-resistant group was much higher than that in the radiation-sensitive group (p<0.001 and p <0.001, respectively). The patients with high expression of SOX2 and OCT4 showed a shorter PFS than those with low expression. Our study suggests that the expression of SOX2 and OCT4 in tumor cells indicates resistance to radiotherapy and that these two factors were important predictors of poor survival in patients with LACSCC (hazard ratio [95% CI], 2.294 [1. 013, 5.195] and 2.300 [1.050, 5.037], respectively; p=0.046 and p=0.037, respectively). (J Histochem Cytochem 62:499-509, 2014)

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“…The radioresistance of human tumor cells can be achieved via aberrantly activated DDR signaling The cells were treated with 2.5 and 5 Gy radiation, and the surviving fraction was calculated based on the number of colonies in the soft agar clonogenic assay. (Shimura et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Time-course analysis of DNA damage response-related genes afterin vitroradiation in H460 and H1229 lung cancer cell lines

et al. 2011

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Radiation is the most useful treatment modality for cancer patients. It initiates a series of signal cascades such as DNA damage response (DDR) signaling for repairing damaged DNA, arresting the cell cycle, and inducing cell death. Until now, few genes have been found to be regulated by radiation, which explains the molecular mechanisms of cellular responses to radiation. Although the transcriptional changes caused by radiation have been widely investigated, little is known about the direct evidence for the transcriptional control of DDR-related genes. Here, we examined the radiosensitivity of two non-small cell lung cancer cell lines (H460 and H1299), which have different p53 status. We monitored the time-dependent changes of 24 DDR-related gene expressions via microarray analysis. Based on the basal expression levels and temporal patterns, we further classified 24 DDR-related genes into four subgroups. Then, we also addressed the protein levels of several DDR-related genes such as TopBP1, Chk1 and Chk2, confirming the results of microarray analysis. Together, these results indicate that the expression patterns of DDR-related genes are associated with radiosensitivity and with the p53 statuses of H460 and H1299, which adds to the understanding of the complex biological responses to radiation.

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Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

Cited by 123 publications

References 45 publications

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors

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

Time-course analysis of DNA damage response-related genes afterin vitroradiation in H460 and H1229 lung cancer cell lines

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