DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway

Fang, Yuan; Chai, Zong‐Tao; Wang, Dansong; Kuang, Tiantao; Wu, Wen-Chuan; Lou, Wenhui

doi:10.1007/s11010-014-2253-6

Cited by 14 publications

(8 citation statements)

References 40 publications

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“…PRKDC is a member of the phosphatidylinositol-3-kinase family 18 . Previous reports have shown that PRKDC is important for AKT activation 19 , 20 . The results of LC-MS/MS showed that KRT80 may interact with PRKDC, so Co-IP assay was performed to test the prediction (Fig.…”

Section: Resultsmentioning

confidence: 94%

Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway

Liu

et al. 2018

Cell Death Dis

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Little is known about the function of Keratin 80 (KRT80), an epithelial keratin, in cancer. This study investigated the role of KRT80 in the prognosis of colorectal carcinoma (CRC) and the underlying mechanisms involved in CRC migration and invasion. We analyzed the expression of KRT80 using The Cancer Genome Atlas and Oncomine databases. Higher expression of KRT80 was found to be significantly associated with multiple pathological parameters, lower disease-free survival, and overall survival in CRC patients. Also, KRT80 was an independent prognostic indicator for CRC. Furthermore, altered KRT80 expression impacted migration and invasion of CRC cells, as well as the expression of epithelial–mesenchymal transition (EMT)-related markers and cell morphology via the AKT pathway. Inhibiting the expression of AKT could reverse these phenomena. Liquid Chromatograph Mass Spectrometer/Mass Spectromete, Co-immunoprecipitation, and laser scanning confocal microscopy techniques showed that KRT80 could interact with protein kinase, DNA-activated, catalytic polypeptide (PRKDC). Suppressing PRKDC could inhibit the expression of AKT and EMT, as well as the migration and invasion of CRC cells. Taken together, these results demonstrated that KRT80 was an independent prognostic biomarker for CRC and promoted CRC migration and invasion by interacting with PRKDC via activation of the AKT pathway.

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Section: Resultsmentioning

confidence: 94%

Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway

Liu

et al. 2018

Cell Death Dis

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“…These findings suggest that the Akt/NF-κB pathway may be able to mediate P-gp expression. Moreover, DNA-PKcs is a member of the PIKK family and is involved in Akt/NF-κB pathway activation (18). Therefore, we postulate that DNA-PKcs is involved in P-gp expression via the Akt/NF-κB pathway in CD133 + MG-63 cells.…”

Section: Discussionmentioning

confidence: 90%

“…Overexpression of DNA-PKcs is found in various malignancies, which is associated with poor prognosis (16,17). However, inhibition of DNA-PKcs sensitizes cells to chemotherapy in various tumor cells including OS (10,18,19). This indicates that DNA-PKcs is correlated with chemoresistance in tumors.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of DNA-PKcs suppresses P-gp expression via inhibition of the Akt/NF-κB pathway in CD133-positive osteosarcoma MG-63 cells

Tian

et al. 2016

Oncology Reports

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The development of chemoresistance is closely linked to the plateau of the survival rate in osteosarcoma (OS) patients. CD133-positive (CD133+) OS cells are known as cancer stem cells (CSCs) in OS and exhibit the characteristic of chemoresistance. In this study, CD133+ and CD133‑negative (CD133‑) MG‑63 cells were isolated by magnetic activated cell sorting (MACS). We verified that CD133+ MG‑63 cells were more resistant to cisplatin (CDDP) than CD133‑ MG‑63 cells. DNA‑dependent protein kinase catalytic subunit (DNA‑PKcs) and P‑glycoprotein (P‑gp) were expressed at higher levels in the CD133+ MG‑63 cells compared with those levels in the CD133‑ MG‑63 cells, whereas downregulation of DNA‑PKcs by small interfering RNA (siRNA) decreased chemoresistance to CDDP and P‑gp expression at the mRNA and protein levels in these cells. This indicated that DNA‑PKcs was correlated with P‑gp expression in the CD133+ MG‑63 cells. The Akt/NF‑κB pathway was hyperactivated in the CD133+ MG‑63 cells, whereas inhibition of the Akt/NF‑κB pathway downregulated P‑gp expression. In addition, downregulation of DNA‑PKcs suppressed the activity of the Akt/NF‑κB pathway. These results revealed that downregulation of DNA‑PKcs could decrease P‑gp expression via suppression of the Akt/NF‑κB pathway in CD133+ MG‑63 cells. Therefore, inhibition of DNA‑PKcs decreases P‑gp expression and sensitizes OS CSCs to chemotherapeutic agents in vitro, which needs to be further validated in vivo.

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“…As one of the PI3K family members, DNA-PK plays an important role in NHEJ to repair DSBs, which are a major mechanism of CDDP cytotoxicity (23). A previous study demonstrated that suppression of DNA-PKcs results in sensitization of HepG2 cells to CDDP treatment (33). In the present study, the western blot results revealed that miR-101 overexpression markedly reduced the expression of DNA-PKcs, as well as phosphorylation of Akt and mTOR.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑101 modulates cisplatin chemoresistance in liver cancer cells via the DNA‑PKcs signaling pathway

et al. 2019

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Due to the high incidence of liver cancer, chemoradiotherapy and prognosis of liver cancer are a primary focus of medical research. microRNAs (miRNAs/miRs) serve crucial roles in resistance to chemotherapy and radiotherapy. The aim of the present study was to investigate the effects of miR-101 on the chemotherapeutic efficacy of cisplatin (CDDP) in liver cancer. First, human liver cancer cells (HepG2) were transfected with a miR-101 mimic or miR-101 inhibitor to bidirectionally regulate the expression of miR-101. Cell proliferation, apoptosis, intracellular reactive oxygen species and comet assay results indicated that the upregulation of miR-101 sensitized HepG2 cells to CDDP, and downregulation of miR-101 reduced chemosensitivity. A xenograft mouse model further confirmed that miR-101 overexpression increased CDDP sensitivity in liver cancer. Luciferase reporter and western blotting assays demonstrated that transfection of the miR-101 mimic markedly reduced activity of the DNA-dependent protein kinase catalytic subunit/protein kinase B/mammalian target of rapamycin (DNA-PKcs/Akt/mTOR) pathway and increased expression of apoptotic protein caspase 3, which is induced by CDDP treatment. By contrast, miR-101 inhibitors partially reversed these changes. Moreover, the miR-101 mimic suppressed activity of the nuclear factor-κB (NF-κB) pathway, leading to increased susceptibility of HepG2 cells to chemotherapeutic agents. In conclusion, miR-101 overexpression augmented cytotoxicity and reduced chemoresistance to CDDP in HepG2 cells, and this was associated with negative regulation of DNA-PKcs/Akt/NF-κB signaling.

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DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway

Cited by 14 publications

References 40 publications

Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway

Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway

Downregulation of DNA-PKcs suppresses P-gp expression via inhibition of the Akt/NF-κB pathway in CD133-positive osteosarcoma MG-63 cells

MicroRNA‑101 modulates cisplatin chemoresistance in liver cancer cells via the DNA‑PKcs signaling pathway

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