Ku70, Ku80, and sClusterin: A Cluster of Predicting Factors for Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer

Pucci, Sabina; Polidoro, Chiara; Joubert, Alessandro; Mastrangeli, Francesca; Tolu, Barbara; Benassi, M.; Fiaschetti, Valeria; Greco, Laura; Miceli, R; Floris, Roberto; Novelli, Giuseppe; Orlandi, Augusto; Santoni, Riccardo

doi:10.1016/j.ijrobp.2016.10.018

Cited by 23 publications

(24 citation statements)

References 13 publications

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“…Depletion of the deubiquitylating enzyme UCHL3 resulted in the reduced chromatin-binding and IR-induced foci (IRIF) formation of Ku80 after DSB occurrence, moderately sensitizing cancer cells to IR 127 . A recent study by Pucci et al 128 reported nuclear localization of Ku in advanced rectal cancer patients with superior sensitivity to radiotherapy. However, in nonresponder patients, Ku70 was found to move from the nucleus to the cytoplasm, and strikingly, deregulation of Ku70/80 and the Ku70 partner clusterin was extensively associated with RR.…”

Section: Cellular Dna Damage Sensors and Early Signal Transducers In Response To Irmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

599

457

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Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.

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Section: Cellular Dna Damage Sensors and Early Signal Transducers In Response To Irmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

599

457

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“…In contrast, Beggs et al reported reduced expression of Ku70 in colon cancer cells, which was associated with higher genomic instability (Beggs et al, 2012). In another study, it was observed that cytoplasmic Ku70 protein levels are higher in patients who do not respond to chemoradiotherapy, while Ku80 was lost in those patients (Pucci et al, 2017). Thus, previous studies have described both overexpression and downregulation of NHEJ pathway genes in colorectal cancer.…”

Section: Discussionmentioning

confidence: 94%

PAXX, Not NHEJ1 Is an Independent Prognosticator in Colon Cancer

Arora

Kumari

Singh

et al. 2020

Front. Mol. Biosci.

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Classical Non-homologous End Joining (NHEJ) pathway is the mainstay of cellular response to DNA double strand breaks. While aberrant expression of genes involved in this pathway has been linked with genomic instability and drug resistance in several cancers, limited information is available about its clinical significance in colon cancer. We performed a comprehensive analysis of seven essential genes, including XRCC5, XRCC6, PRKDC, LIG4, XRCC4, NHEJ1, and PAXX of this pathway, in colon cancer using multi-omics datasets, and studied their associations with molecular and clinicopathological features, including age, gender, stage, KRAS mutation, BRAF mutation, microsatellite instability status and promoter DNA methylation in TCGA colon cancer dataset. This analysis revealed upregulation of XRCC5, PRKDC, and PAXX in colon cancer compared to normal colon tissues, while LIG4 and NHEJ1 (XLF) displayed downregulation. The expression of these genes was independent of age and KRAS status, while XRCC5, PRKDC, and LIG4 exhibited reduced expression in BRAF mutant tumors. Interestingly, we observed a strong association between XRCC6, XRCC5, PRKDC and LIG4 overexpression and microsatellite instability status of the tumors. In multivariate analysis, high PAXX expression emerged as an independent prognostic marker for poor overall and disease specific survival. We also observed hypomethylation of PAXX promoter in tumors, which exhibited a strong correlation with its overexpression. Furthermore, PAXX overexpression was also associated with several oncogenic pathways as well as a reduction in numbers of tumor-infiltrating lymphocytes.

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“…Ku70 has been demonstrated to be upregulated in some cell types in response to DNA damage [29, 30, 73]. In some systems, it is believed that Ku70 is highly expressed, and may not be subject to regulation by DNA damage [74, 75]. Because of this controversy, we first compared the levels of basal Ku70 expression in NHAs and MSCs with that in two cancer cell lines that express high levels of Ku70 (A549 and HEK293) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Radiation resistance of normal human astrocytes: the role of non-homologous end joining DNA repair activity

Bylicky

Mueller

Day

2018

Journal of Radiation Research

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Radiotherapy is a common modality for treatment of brain cancers, but it can induce long-term physiological and cognitive deficits. The responses of normal human brain cells to radiation is not well understood. Astrocytes have been shown to have a variety of protective mechanisms against oxidative stress and have been shown to protect neurons. We investigated the response of cultured normal human astrocytes (NHAs) to X-ray irradiation. Following exposure to 10 Gy X-irradiation, NHAs exhibited DNA damage as indicated by the formation of γ-H2AX foci. Western blotting showed that NHAs displayed a robust increase in expression of non-homologous end joining DNA repair enzymes within 15 min post-irradiation and increased expression of homologous recombination DNA repair enzymes ~2 h post-irradiation. The cell cycle checkpoint protein p21/waf1 was upregulated from 6–24 h, and then returned to baseline. Levels of DNA repair enzymes returned to basal ~48 h post-irradiation. NHAs re-entered the cell cycle and proliferation was observed at 6 days. In contrast, normal human mesenchymal stem cells (MSCs) failed to upregulate DNA repair enzymes and instead displayed sustained upregulation of p21/waf1, a cell cycle checkpoint marker for senescence. Ectopic overexpression of Ku70 was sufficient to protect MSCs from sustained upregulation of p21/waf1 induced by 10 Gy X-rays. These findings suggest that increased expression of Ku70 may be a key mechanism for the radioresistance of NHAs, preventing their accelerated senescence from high-dose radiation. These results may have implications for the development of novel targets for radiation countermeasure development.

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Ku70, Ku80, and sClusterin: A Cluster of Predicting Factors for Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer

Cited by 23 publications

References 13 publications

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

PAXX, Not NHEJ1 Is an Independent Prognosticator in Colon Cancer

Radiation resistance of normal human astrocytes: the role of non-homologous end joining DNA repair activity

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