title: Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma.
abstract: Human papillomavirus (HPV) DNA integrations may affect therapeutic responses in cancers through ATM network-related DNA damage response (DDR). We studied whether cisplatin-induced DDR was altered in human HK-2 renal tubular cells immortalized by HPV16 E6/E7 genes. Cytotoxicity assays utilized thiazolyl blue dye and DDR was identified by gene expression differences, double-strand DNA breaks, ATM promoter activity, and analysis of cell cycling and side population cells. After cisplatin, HK-2 cells showed greater ATM promoter activity indicating activation of this network, but DDR was muted, since little γH2AX was expressed, DNA strand breaks were absent and cells continued cycling. When HK-2 cells were treated with the MDM2 antagonist inducing p53, nutlin-3, or p53 transcriptional activator, tenovin-1, cell growth decreased but cisplatin toxicity was unaffected. By contrast, arsenic trioxide, which by inhibiting wild-type p53-induced phosphatase-1 that serves responses downstream of p53, and by depolymerizing tubulin, synergistically enhanced cisplatin cytotoxicity including loss of SP cells. Our findings demonstrated that HPV16 E6/E7 altered DDR through p53-mediated cell growth controls, which may be overcome by targeting of WIP1 and other processes, and thus should be relevant for treating renal cell carcinoma.
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Children's Hospital at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Samriti
authors.initials: S
authors.lastname: Dogra
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Bandi
authors.affiliation: Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Viswanathan
authors.affiliation: Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Diabetes Center, Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: sanjeev.gupta@einstein.yu.edu.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002472:Cell Transformation, Viral / Q000187:drug effects* / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004357:Drug Synergism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000821:virology; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000235:genetics / Q000821:virology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C068651:E6 protein, Human papillomavirus type 16; C468783:H2AX protein, human; D006657:Histones; D009856:Oncogene Proteins, Viral; D010087:Oxides; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D002945:Cisplatin; D000077237:Arsenic Trioxide
keywords: Ataxia telangiectasia mutated; Chemotherapy; DNA damage response; Nephrotoxicity; Renal cell carcinoma