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Fluorescence Microscopy for ATP Internalization Mediated by Macropinocytosis in Human Tumor Cells and Tumor-xenografted Mice
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Inhibition of tumor cell surface ATP synthesis by pigment epithelium-derived factor: implications for antitumor

Monika Deshpande1, Luigi Notari, Preeti Subramanian

  • 1Section of Protein Structure and Function, Laboratory of Retinal Cell and Molecular Biology, NEI-NIH, Bethesda, MD, USA.

International Journal of Oncology
|April 17, 2012
PubMed

Insights

Pigment epithelium-derived factor (PEDF) inhibits tumor cell surface ATP synthase, reducing tumor viability. A specific peptide region (34-mer) of PEDF is responsible for this cytotoxic effect on cancer cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Pigment epithelium-derived factor (PEDF) is an antiangiogenic protein with known tumor-restricting properties.
  • Active cell surface ATP synthase is present in tumor cells and its product, ATP, may stimulate tumor growth.
  • Previous studies showed PEDF inhibits endothelial cell surface ATP synthase.

Purpose of the Study:

  • To investigate the biological effects of extracellular PEDF on tumor cell surface ATP synthase.
  • To determine if PEDF can inhibit ATP synthase activity on tumor cells and impact their viability.
  • To identify the specific region of PEDF responsible for these effects.

Main Methods:

  • Incubation of T24 human urinary bladder carcinoma cells with recombinant PEDF.
  • Monitoring cell viability using real-time cell impedance, microscopic imaging, and live cell biomarkers.
  • Assessing cell surface ATP synthesis activity and inhibition using specific inhibitors (piceatannol) and immunoblotting for F1-ATP synthase β subunit.
  • Testing the effect of a PEDF-derived peptide (34-mer) and exogenous ATP.

Main Results:

  • PEDF significantly decreased T24 cell viability in a concentration-dependent manner.
  • Tumor cell surface ATP synthesis activity was inhibited by PEDF, with the β subunit of F1-ATP synthase detected in plasma membrane fractions.
  • The PEDF 34-mer peptide mimicked the effects of full-length PEDF on cell viability and extracellular ATP synthesis.
  • Exogenous ATP partially reversed PEDF's effects on tumor cell viability and endothelial cell tube formation.

Conclusions:

  • PEDF is a novel inhibitor of tumor cell surface ATP synthase activity.
  • PEDF exhibits a cytotoxic effect on tumor cells, mediated by the inhibition of cell surface ATP synthase.
  • The PEDF 34-mer peptide contains the structural determinants responsible for inhibiting tumor cell surface ATP synthase and inducing cytotoxicity.

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