title: DNA-PKcs: A promising therapeutic target in human hepatocellular carcinoma?
abstract: Hepatocellular carcinoma (HCC) is a frequent and deadly disease worldwide. The absence of effective therapies when the tumor is surgically unresectable leads to an extremely poor outcome of HCC patients. Thus, it is mandatory to elucidate the molecular pathogenesis of HCC in order to develop novel therapeutic strategies against this pernicious tumor. Mounting evidence indicates that suppression of the DNA damage response machinery might be deleterious for the survival and growth of the tumor cells. In particular, DNA dependent protein kinase catalytic subunit (DNA-PKcs), a major player in the non-homologous end-joining (NHEJ) repair process, seems to represent a valuable target for innovative anti-neoplastic therapies in cancer. DNA-PKcs levels are strongly upregulated and associated with a poor clinical outcome in various tumor types, including HCC. Importantly, DNA-PKcs not only protects tumor cells from harmful DNA insults coming either from the microenvironment or chemotherapeutic drug treatments, but also possesses additional properties, independent from its DNA repair activity, that provide growth advantages to cancer cells. These properties (metabolic and gene reprogramming, invasiveness and metastasis, resistance to apoptosis, etc.) have started to be elucidated. In the present review, we summarize the physiologic and oncogenic roles of DNA-PKcs, with a special emphasis on liver cancer. In particular, this work focuses on the molecular mechanism whereby DNA-PKcs exerts its pro-tumorigenic activity in cancer cells. In addition, the upstream regulator of DNA-PKcs activation as well as its downstream effectors thus far identified are illustrated. Furthermore, the potential therapeutic strategies aimed at inhibiting DNA-PKcs activity in HCC are discussed.
authors: Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy.
authors: Rosa M
authors: RM
authors: Pascale
authors: Institute of Pathology, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
authors: Christy
authors: C
authors: Joseph
authors: Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy.
authors: Gavinella
authors: G
authors: Latte
authors: Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.
authors: Matthias
authors: M
authors: Evert
authors: Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy.
authors: Francesco
authors: F
authors: Feo
authors: Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy; Institute of Pathology, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. Electronic address: calvisid@uniss.it.
authors: Diego F
authors: DF
authors: Calvisi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D002867:Chromones / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D059766:DNA End-Joining Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013876:Thiophenes / Q000627:therapeutic use; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D002867:Chromones; D004273:DNA, Neoplasm; D051747:DNA-Activated Protein Kinase; D009025:Morpholines; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013876:Thiophenes; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1; C576809:2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo(b,d)thiophen-1-yl)acetamide; C499693:8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; C111164:BRAP protein, human; C578634:CHEK2 protein, human; C497263:PRKDC protein, human
keywords: DNA repair; Hepatocellular carcinoma; Signaling pathways; Targeted therapies