Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells

Patrick D. Sutphin, Denise A. Chan, James M. Li, Sandra Turcotte, Adam J. Krieg, Amato J. Giaccia

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Late-stage clear cell renal carcinoma poses a formidable clinical challenge due to the high mortality rate associated with this disease. Molecular and genetic studies have identified functional loss of the von Hippel-Lindau (VHL) gene as a frequent and crucial event in the development of the malignant phenotype of clear cell renal carcinomas. Loss of VHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. The objective of this study was to evaluate the possibility of targeting VHL loss through pharmacologic means. Chromomycin A3 (ChA3) was identified through in silico analysis of existing publicly available drug profiles from the National Cancer Institute as an agent that seemed to selectively target VHL-deficient clear cell renal carcinoma cells. Genotype-selective toxicity was first determined through short-term viability assays and then confirmed with clonogenic studies. Coculture of fluorescently labeled VHL-deficient and VHL-positive cells showed discriminate killing of the VHL-deficient cells with ChA3. Mechanistically, overexpression of hypoxia-inducible factor (HIF)-2α in VHL-positive clear cell renal carcinoma cells phenocopied loss of VHL with respect to ChA3 toxicity, establishing ChA3 as a HIF-dependent cytotoxin. This study shows the feasibility of selectively targeting the loss of the VHL tumor suppressor gene in clear cell renal carcinoma for potential clinical benefit and may have greater ramifications in the development of new targeted therapies for the treatment of cancer and other genetic diseases.

Original languageEnglish (US)
Pages (from-to)5896-5905
Number of pages10
JournalCancer Research
Volume67
Issue number12
DOIs
StatePublished - Jun 15 2007

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Chromomycin A3
Tumor Suppressor Genes
Renal Cell Carcinoma
Inborn Genetic Diseases
National Cancer Institute (U.S.)
Cytotoxins
Feasibility Studies
Coculture Techniques
Computer Simulation
Molecular Biology
Genotype
Phenotype
Mortality
Therapeutics
Pharmaceutical Preparations
Genes
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sutphin, P. D., Chan, D. A., Li, J. M., Turcotte, S., Krieg, A. J., & Giaccia, A. J. (2007). Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells. Cancer Research, 67(12), 5896-5905. https://doi.org/10.1158/0008-5472.CAN-07-0604

Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells. / Sutphin, Patrick D.; Chan, Denise A.; Li, James M.; Turcotte, Sandra; Krieg, Adam J.; Giaccia, Amato J.

In: Cancer Research, Vol. 67, No. 12, 15.06.2007, p. 5896-5905.

Research output: Contribution to journalArticle

Sutphin, PD, Chan, DA, Li, JM, Turcotte, S, Krieg, AJ & Giaccia, AJ 2007, 'Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells', Cancer Research, vol. 67, no. 12, pp. 5896-5905. https://doi.org/10.1158/0008-5472.CAN-07-0604
Sutphin, Patrick D. ; Chan, Denise A. ; Li, James M. ; Turcotte, Sandra ; Krieg, Adam J. ; Giaccia, Amato J. / Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells. In: Cancer Research. 2007 ; Vol. 67, No. 12. pp. 5896-5905.
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