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Cancer Lett. 2015 Jan 28;356(2 Pt B):953-61. doi: 10.1016/j.canlet.2014.11.008. Epub 2014 Nov 10.

Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma.

Author information

1
Division of Pediatric Nephrology, Department of Pediatrics, Children's Hospital at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
2
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
3
Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
4
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.

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.

KEYWORDS:

Ataxia telangiectasia mutated; Chemotherapy; DNA damage response; Nephrotoxicity; Renal cell carcinoma

PMID:
25444910
PMCID:
PMC4259818
DOI:
10.1016/j.canlet.2014.11.008
[Indexed for MEDLINE]
Free PMC Article

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