Suppression of DNA-PKcs and Ku80 individually and in combination: Different effects of radiobiology in HeLa cells

Huang, Xiaoyuan

doi:10.3892/ijo.2011.1041

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…The results indicated that the rate of apoptosis of HeLa/Ku80-siRNA cells following 6 Gy 6 MV X-ray irradiation at 48 and 72 h increased, whereas the SF2 and D 0 values obtained from clonogenic survival assays decreased. These results suggested that the HeLa cells with Ku80 inhibition become more radiosensitive, similar to the results of previous studies ( 17 – 19 ).…”

Section: Discussionsupporting

confidence: 91%

Effect of Ku80 on the radiosensitization of cisplatin in the cervical carcinoma cell line HeLa

et al. 2017

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Cisplatin chemotherapy in combination with radiotherapy is the primary therapeutic strategy for the treatment of cervical cancer; however, the underlying molecular mechanism for cisplatin radiosensitization remains unknown. The aim of the present study was to investigate the effect of Ku80, a DNA double-strand break (DSB) repair protein, on cisplatin radiosensitization in cervical cancer. The pre-established Ku80 suppression cervical cancer cell line HeLa/Ku80-siRNA and the normal HeLa cell line underwent 6 MV X-ray irradiation (6 Gy) individually or in combination with 5 µg/ml cisplatin treatment. Alterations in apoptosis, the cell cycle and γH2AX expression were detected. Following irradiation individually and combined with cisplatin, compared with normal HeLa cells, HeLa/Ku80-siRNAexhibited an increased rate of apoptosis (P<0.05). It was identified that the earlier cisplatin was administered following irradiation, the higher the rate of apoptosis. Cell cycle analysis indicated that, following irradiation combined with cisplatin, the cells were arrested in G1 and S phase rather than in G2/M phase following irradiation alone. Microscopic imaging of immunofluorescence staining and western blotting identified that HeLa/Ku80-siRNA cells exhibited more γH2AX foci remaining following treatment with irradiation and cisplatin, particularly in the group treated with 6 Gy irradiation for 1 h together with 23 h of exposure to cisplatin. Irradiation in combination with cisplatin promoted the apoptosis of HeLa cells in association with the inhibition of Ku80, and it was identified that the earlier cisplatin was administered following irradiation, the more apoptosis was induced. This maybe because irradiation combined with cisplatin is able to arrest cells in G1 and S phase to rapidly repair damaged DNA, and the lack of Ku80 induces the inability to repair DSB, resulting in increased apoptosis. The results of the present study suggest that Ku80 may be a potent molecular target in cisplatin radiosensitization.

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Section: Discussionsupporting

confidence: 91%

Effect of Ku80 on the radiosensitization of cisplatin in the cervical carcinoma cell line HeLa

et al. 2017

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“…The cell-permeable compound LY294002, on the other hand, acts on the ATP-binding site of PI3K proteins and inhibits DNA-PKcs in a competitive manner. The apoptotic rate of X-ray irradiated HeLa cells after pre-treatment with LY294002 was found to be significantly higher than that of untreated cells, with a prolonged G2/M delay also observed in these cells ( 63 ). IC87361 is a morpholino-flavonoid that has been derived from LY294002, and which is 50-fold more selective for DNA-PKcs than for PI3K and other kinases.…”

Section: Dna-pkcs As a Therapeutic Target For Ovarian Cancermentioning

confidence: 98%

Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy

2015

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Platinum-based chemotherapy is the cornerstone of ovarian cancer treatment, and its efficacy is dependent on the generation of DNA damage, with subsequent induction of apoptosis. Inappropriate or aberrant activation of the DNA damage response network is associated with resistance to platinum, and defects in DNA repair pathways play critical roles in determining patient response to chemotherapy. In ovarian cancer, tumor cell defects in homologous recombination – a repair pathway activated in response to double-strand DNA breaks (DSB) – are most commonly associated with platinum-sensitive disease. However, despite initial sensitivity, the emergence of resistance is frequent. Here, we review strategies for directly interfering with DNA repair pathways, with particular focus on direct inhibition of non-homologous end joining (NHEJ), another DSB repair pathway. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a core component of NHEJ and it has shown considerable promise as a chemosensitization target in numerous cancer types, including ovarian cancer where it functions to promote platinum-induced survival signaling, via AKT activation. The development of pharmacological inhibitors of DNA-PKcs is on-going, and clinic-ready agents offer real hope to patients with chemoresistant disease.

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“…The NHEJ pathway is regarded as the major pathway for the repair of radiation induced DSBs in mammalian cells [ 11 – 15 ]. One of the main participants in this pathway is the DNA-dependent protein kinase (DNA-PK) that consists of a large catalytic subunit, DNA-PKcs, and a heterodimeric protein named Ku, which is a highly stable protein complex consisting of a 70 kDa and a 86 kDa polypeptide, better known as Ku70 and Ku80 [ 16 – 20 ]. NHEJ is initiated by the DNA repair protein Ku, which recognizes DSBs and recruits additional pathway components to process and repair the damage.…”

Section: Introductionmentioning

confidence: 99%

Hyperthermia Induces Apoptosis of 786-O Cells through Suppressing Ku80 Expression

et al. 2015

PLoS ONE

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Hyperthermia as an anticancer method has been paid increasing attention in recent years. Several studies have shown that hyperthermia can kill tumor cells by inducing apoptosis. However, the underlying molecular mechanisms of hyperthermia-induced apoptosis are largely unknown. To investigate the effects and molecular mechanism of hyperthermia on the apoptosis in renal carcinoma 786-O cells, we firstly examined apoptosis and Ku expression in 786-O cell line treated with heat exposure (42°C for 0-4 h). The results showed that hyperthermia induced apoptosis of 786-O cells, and suppressed significantly Ku80 expression, but not Ku70 expression. Next, we knock-down Ku80 in 786-O cells, generating stable cell line 786-O-shKu80, and detected apoptosis, cell survival and cell cycle distribution. Our data showed higher apoptotic rate and lower surviving fraction in the stable cell line 786-O-shKu80 compared with those in control cells, exposed to the same heat stress (42°C for 0-4 h). Moreover, the results also showed suppression of Ku80 led to G2/M phase arrest in the stable cell line 786-O-shKu80 following heat treatment. Together, these findings indicate that Ku80 may play an important role in hyperthermia-induced apoptosis and heat-sensitivity of renal carcinoma cells through influencing the cell cycle distribution.

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Suppression of DNA-PKcs and Ku80 individually and in combination: Different effects of radiobiology in HeLa cells

Cited by 5 publications

References 33 publications

Effect of Ku80 on the radiosensitization of cisplatin in the cervical carcinoma cell line HeLa

Effect of Ku80 on the radiosensitization of cisplatin in the cervical carcinoma cell line HeLa

Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy

Hyperthermia Induces Apoptosis of 786-O Cells through Suppressing Ku80 Expression

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