ArticleOncotarget2016
KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 40 citations in OpenAlex.
- Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Identification of G protein subunit alpha i2 as a promising therapeutic target of hepatocellular carcinoma.Cell death & disease · 2023Article
- Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy.International journal of molecular sciences · 2022Review
- Interactions between miRNAs and Double-Strand Breaks DNA Repair Genes, Pursuing a Fine-Tuning of Repair.International journal of molecular sciences · 2022Review
- Elevated expression of nuclear receptor-binding SET domain 3 promotes pancreatic cancer cell growth.Cell death & disease · 2021Article
- HBO1 overexpression is important for hepatocellular carcinoma cell growth.Cell death & disease · 2021Article
- Dual inhibition of DNA-PKcs and mTOR by CC-115 potently inhibits human renal cell carcinoma cell growth.Aging · 2020Article
- Integrated multi-omics data analysis identifying novel drug sensitivity-associated molecular targets of hepatocellular carcinoma cells.Oncology letters · 2018Article
- AMPK activation by Tanshinone IIA protects neuronal cells from oxygen-glucose deprivation.Oncotarget · 2018Article
- Article
- Kaempferol induces autophagic cell death of hepatocellular carcinoma cells via activating AMPK signaling.Oncotarget · 2017Article
- ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activityOncotarget · 2017Article
- Silencing protein kinase C ζ by microRNA-25-5p activates AMPK signaling and inhibits colorectal cancer cell proliferation.Oncotarget · 2017Article
- Preclinical study of CC223 as a potential anti-ovarian cancer agent.Oncotarget · 2017Article
- Tumor-specific hepatic stellate cells (tHSCs) induces DIgR2 expression in dendritic cells to inhibit T cells.Oncotarget · 2017Article
- Ulk1 over-expression in human gastric cancer is correlated with patients' T classification and cancer relapse.Oncotarget · 2017Article
- A reproducible model of intramedullary spinal cord tumor in rats bearing RG2 cells.Oncotarget · 2017Article
- AMPKα phosphatase Ppm1E upregulation in human gastric cancer is required for cell proliferation.Oncotarget · 2017Article
- Identification of DNA-PKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells.Oncotarget · 2017Article
- Identification of sphingosine kinase 1 (SphK1) as a primary target of icaritin in hepatocellular carcinoma cells.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
10 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Here we tested anti-tumor activity of KU-0060648 in preclinical hepatocellular carcinoma (HCC) models. Our results demonstrated that KU-0060648 was anti-proliferative and pro-apoptotic in established (HepG2, Huh-7 and KYN-2 lines) and primary human HCC cells, but was non-cytotoxic to non-cancerous HL-7702 hepatocytes. DNA-PKcs (DNA-activated protein kinase catalytic subunit) is an important but not exclusive target of KU-0060648. DNA-PKcs knockdown or dominant negative mutation inhibited HCC cell proliferation. On the other hand, overexpression of wild-type DNA-PKcs enhanced HepG2 cell proliferation. Importantly, KU-0060648 was still cytotoxic to DNA-PKcs-silenced or -mutated HepG2 cells, although its activity in these cells was relatively weak. Further studies showed that KU-0060648 inhibited PI3K-AKT-mTOR activation, independent of DNA-PKcs. Introduction of constitutively-active AKT1 (CA-AKT1) restored AKT-mTOR activation after KU-0060648 treatment in HepG2 cells, and alleviated subsequent cytotoxicity. In vivo, intraperitoneal (i.p.) injection of KU-0060648 significantly inhibited HepG2 xenograft growth in nude mice. AKT-mTOR activation was also inhibited in xenografted tumors. Finally, we showed that DNA-PKcs expression was significantly upregulated in human HCC tissues. Yet miRNA-101, an anti-DNA-PKcs miRNA, was downregulated. Over-expression of miR-101 in HepG2 cells inhibited DNA-PKcs expression and cell proliferation. Together, these results indicate that KU-0060648 inhibits HCC cells through DNA-PKcs-dependent and -independent mechanisms.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.