Targeting DNA-PKcs increased anticancer drug sensitivity by suppressing DNA damage repair in osteosarcoma cell line MG63

Li, Xin; Tian, Jing; Bo, Qiyu; Li, Ka; Wang, Hongliang; Liu, Ting; Li, Jianmin

doi:10.1007/s13277-015-3642-5

Cited by 20 publications

(16 citation statements)

References 30 publications

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“…16 PRKDC (alias: DNA-PKC, DNA-PKcs) has been reported to regulate cell proliferation, cell cycle, and apoptosis in multiple cancers. [31][32][33] Additionally, the previous study has shown that PRKDC was related to radio-resistance in ESCC. 34 Concordantly, we confirmed the upregulation of PRKDC in ESCC cell lines and that miR-488-3p targeted PRKDC in ESCC cells.…”

Section: Discussionmentioning

confidence: 93%

“…A former study demonstrated that miR‐488‐3p targeted PRKDC, known as a regulator of DNA damage repair, to enhance radiosensitivity in melanoma . PRKDC (alias: DNA‐PKC, DNA‐PKcs) has been reported to regulate cell proliferation, cell cycle, and apoptosis in multiple cancers . Additionally, the previous study has shown that PRKDC was related to radio‐resistance in ESCC .…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA‐488‐3p inhibits proliferation and induces apoptosis by targeting ZBTB2 in esophageal squamous cell carcinoma

Yang

et al. 2019

J of Cellular Biochemistry

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Esophageal squamous cell carcinoma (ESCC) is the eighth most prevalent cancer and the sixth leading cause for cancer‐associated mortality. MicroRNAs (miRNAs) are increasingly reported to exert important regulatory functions in human cancers by regulating certain gene expression. miR‐488‐3p has been identified to be a tumor suppressor in multiple cancers, but its role in ESCC is yet to be investigated. The present study aimed to uncover the biological role and modulatory mechanism of miR‐488‐3p in ESCC. We first revealed the downregulation of miR‐488‐3p in ESCC tissues and cell lines. Gain‐of‐function assays confirmed that miR‐488‐3p overexpression abrogated proliferation and accelerated apoptosis. Mechanistically, we identified via bioinformatics tool and confirmed that zinc finger and BTB domain containing 2 (ZBTB2) was a target for miR‐488‐3p. Moreover, miR‐488‐3p activated the p53 pathway through suppressing ZBTB2. Finally, rescue assays proved that ZBTB2 was involved in the regulation of miR‐488‐3p on proliferation and apoptosis in ESCC. Additionally, we verified that miR‐488‐3p had alternate targets in ESCC by confirming the involvement of protein kinase, DNA‐activated, catalytic subunit (PRKDC), a known target for miR‐488‐3p, in miR‐488‐3p‐mediated regulation on ESCC. In sum, this study revealed that miR‐488‐3p inhibited proliferation and induced apoptosis by targeting ZBTB2 and activating p53 pathway in esophageal squamous cell carcinoma, providing a novel biological target for ESCC.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

MicroRNA‐488‐3p inhibits proliferation and induces apoptosis by targeting ZBTB2 in esophageal squamous cell carcinoma

Yang

et al. 2019

J of Cellular Biochemistry

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“…After the induction of a DSB, the Ku heterodimer [composed of polypeptides of about 70 (Ku70) and 80 kDa (Ku80)] binds DNA break ends and recruits the DNA-PKcs. DNA-PKcs induces recruitment of repair proteins to DSBs and activation of checkpoints, which leads to the formation of the DNA-PK holo-enzyme [39,40] . DNA-PK then forms a functional complex with Artemis, which provides nucleolytic processing activity required to prepare DNA ends for ligation [41] .…”

Section: Inhibition Of Dna-pkcs and Ku70/80mentioning

confidence: 99%

“…DNA-PK then forms a functional complex with Artemis, which provides nucleolytic processing activity required to prepare DNA ends for ligation [41] . Many studies showed that cells deficient in DNA-PK exhibit hypersensitivity to IR [40] . Radiosensitization has been observed with wortmannin [42] which is the first identified DNA-PK inhibitor.…”

Section: Inhibition Of Dna-pkcs and Ku70/80mentioning

confidence: 99%

The Inhibition of DNA Damage Response Contributes to Cancer Radiotherapy

Sun¹,

Chen²,

Hu³

2018

International Journal of Radiology

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The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. More than 50 % of cancer patients will receive some kinds of radiotherapy during their treatment process, either alone or in combination with other treatment modalities. Targeted therapy based on inhibiting the DDR in cancers offers a greater treatment pathway to patients with tumors by impeding DSBs repair. These have led to the development of radiotherapy combined with pharmacological interventions, which are more specifically targeting tumor, leading to the improvements in cancer therapeutic efficacy. This review highlights the different target DDR proteins' inhibitors in cancer and how this can provide significant opportunities for DDR-based sensitivity of radiotherapies in the future.

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“…While some studies have explored the use of DNA-PK CS inhibitors to sensitize OS cells to chemotherapy [15, 16], the role of these inhibitors in sensitizing OS cells to IR remains to be investigated. KU60648 is a recently developed potent small molecule DNA-PK CS inhibitor [17].…”

Section: Introductionmentioning

confidence: 99%

Inhibiting DNA-PKCS radiosensitizes human osteosarcoma cells

Mamo

Mladek

Shogren

et al. 2017

Biochemical and Biophysical Research Communications

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Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PKCS), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PKCS in osteosarcoma tissue specimens and cell lines was examined. Moreover, the small molecule DNA-PKCS inhibitor, KU60648, was investigated as a radiosensitizing strategy for osteosarcoma cells in vitro. DNA-PKCS was consistently expressed in the osteosarcoma tissue specimens and cell lines studied. Additionally, KU60648 effectively sensitized two of those osteosarcoma cell lines (143B cells by 1.5-fold and U2OS cells by 2.5-fold). KU60648 co-treatment also altered cell cycle distribution and enhanced DNA damage. Cell accumulation at the G2/M transition point increased by 55% and 45%, while the percentage of cells with >20 γH2AX foci were enhanced by 59% and 107% for 143B and U2OS cells, respectively. These results indicate that the DNA-PKCS inhibitor, KU60648, is a promising radiosensitizing agent for osteosarcoma.

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Targeting DNA-PKcs increased anticancer drug sensitivity by suppressing DNA damage repair in osteosarcoma cell line MG63

Cited by 20 publications

References 30 publications

MicroRNA‐488‐3p inhibits proliferation and induces apoptosis by targeting ZBTB2 in esophageal squamous cell carcinoma

MicroRNA‐488‐3p inhibits proliferation and induces apoptosis by targeting ZBTB2 in esophageal squamous cell carcinoma

The Inhibition of DNA Damage Response Contributes to Cancer Radiotherapy

Inhibiting DNA-PKCS radiosensitizes human osteosarcoma cells

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