Extracellular matrix and HIF-1 signaling: The role of prolidase

Authors

  • Arkadiusz Surazynski,

    1. Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD
    2. Deparatment of Medicinal Chemistry, Medical University in Bialylstok, Poland
    Search for more papers by this author
    • The first two authors contributed equally to this paper.

  • Steven P. Donald,

    1. Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD
    Search for more papers by this author
    • The first two authors contributed equally to this paper.

  • Sandra K. Cooper,

    1. Basic Research Program, SAIC-Frederick, Frederick, MD
    Search for more papers by this author
  • Martin A. Whiteside,

    1. Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD
    Search for more papers by this author
    • Martin A. Whiteside is a Cancer Prevention Fellow, DCP, NCI.

  • Konstantin Salnikow,

    1. Metals Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD
    Search for more papers by this author
  • Yongmin Liu,

    Corresponding author
    1. Basic Research Program, SAIC-Frederick, Frederick, MD
    • Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Building 538, Room 144. National Cancer Institute at Frederick, Frederick, Maryland 21702, USA
    Search for more papers by this author
    • Fax: (301) 846-6093.

  • James M. Phang

    Corresponding author
    1. Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD
    • Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Building 538, Room 144. National Cancer Institute at Frederick, Frederick, Maryland 21702, USA
    Search for more papers by this author

Abstract

Hypoxia-inducible factor-1 (HIF-1) plays an important role in stress-responsive gene expression. Although primarily sensitive to hypoxia, HIF-1 signaling can be regulated by a number of stress factors including metabolic stress, growth factors and molecules present in the extracellular matrix (ECM). Degradation of ECM by metalloproteinases (MMP) is important for tumor progression, invasion and metastasis. ECM is predominantly collagen, and the imino acids (Pro and HyPro) comprise 25% of collagen residues. The final step in collagen degradation is catalyzed by prolidase, the obligate peptidase for imidodipeptides with Pro and HyPro in the carboxyl terminus. Defective wound healing in patients with inherited prolidase deficiency is associated with histologic features of angiopathy suggesting that prolidase may play a role in angiogenesis. Because HIF-1α is central to angiogenesis, we considered that prolidase may modulate this pathway. To test this hypothesis, we made expression constructs of human prolidase and obtained stable transfectants in colorectal cancer cells (RKO). Overexpression of prolidase resulted in increased nuclear hypoxia inducible factor (HIF-1α) levels and elevated expression of HIF-1−dependent gene products, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). The activation of HIF-1-dependent transcription was shown by prolidase-dependent activation of hypoxia response element (HRE)-luciferase expression. We used an oxygen-dependent degradation domain (ODD)-luciferase reporter construct as a surrogate for HIF-1α as an in situ prolyl-hydroxylase assay. Since this reporter is degraded by VHL-dependent mechanisms, the increased levels of luciferase observed with prolidase expression reflected the decreased HIF-1α prolyl hydroxylase activity. Additionally, the differential expression of prolidase in 2 breast cancer cell lines showed prolidase-dependent differences in HIF-1α levels. These findings show that metabolism of imidodipeptides by prolidase plays a previously unrecognized role in angiogenic signaling. © 2007 Wiley-Liss, Inc.

Ancillary