Suppression of VEGF transcription in renal cell carcinoma cells by pyrrole-imidazole hairpin polyamides targeting the hypoxia responsive element

Authors

  • Yukio Kageyama Department of Urology, Graduate School of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
  • Hiroshi Sugiyama Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Surugadai, Kanda, Chiyoda-ku, Tokyo, 101-0062, Japan; Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa Oiwakecho, Sakyo-ku, Kyoto, 606-8502, Japan
  • Hirohito Ayame Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Surugadai, Kanda, Chiyoda-ku, Tokyo, 101-0062, Japan
  • Aki Iwai Department of Urology, Graduate School of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
  • Yasuhisa Fujii Department of Urology, Graduate School of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
  • L. Eric Huang Laboratory of Human Carcinogenesis, NCI, National Institute of Health, Bethesda, MD, USA
  • Shinae Kizaka-Kondoh Department of Therapeutic Radiology and Oncology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Kyoto, 606-8507, Japan
  • Masahiro Hiraoka Department of Therapeutic Radiology and Oncology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Kyoto, 606-8507, Japan
  • Kazunori Kihara Department of Urology, Graduate School of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

DOI:

https://doi.org/10.1080/02841860500486648

Abstract

Hypoxia inducible factor (HIF), a master regulator of critical genes for cell survival under hypoxic conditions, is known to be related to tumorigenesis and progression of renal cell carcinoma. N-methylpyrrole (Py)-N-methylimidazole (Im) hairpin polyamides are synthetic organic compounds that recognize and bind to the minor grooves of specific DNA sequences. We synthesized three Py-Im hairpin polyamides targeting the flanking sequences of hypoxia responsive element (HRE; a binding site of HIF) in the promoter region of the vascular endothelial growth factor (VEGF) gene. The effects of the polyamides on HIF-induced transcription were evaluated by a luciferase assay using a reporter plasmid containing a VEGF promoter. Real time reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay were performed to examine the effects of the polyamides on the transcription and secretion of VEGF in A498 renal cell carcinoma cells, which have a frame-shift mutation in the von Hippel-Lindau gene. A combination of three Py-Im hairpin polyamides suppressed HIF-induced transcription in reporter assays using 293 cells and successfully suppressed transcription and translation of the VEGF gene in A498 cells. Inhibition of the HIF-HRE interaction was confirmed by an electrophoresis mobility shift assay. An approach using Py-Im hairpin polyamides may be a new strategy for the treatment of renal cell carcinoma.

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Published

2006-01-01

How to Cite

Kageyama, Y., Sugiyama, H., Ayame, H., Iwai, A., Fujii, Y., Huang, L. E., … Kihara, K. (2006). Suppression of VEGF transcription in renal cell carcinoma cells by pyrrole-imidazole hairpin polyamides targeting the hypoxia responsive element. Acta Oncologica, 45(3), 317–324. https://doi.org/10.1080/02841860500486648

Issue

Vol. 45 No. 3 (2006): Acta Oncologica

Section

Articles