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PAPA-1 Is a nuclear binding partner of IGFBP-2 and modulates its growth-promoting actions

Kenichi Miyako1, Laura J Cobb, Malik Francis

  • 1David Geffen School of Medicine at University of California, Los Angeles, California 90095-1752, USA.

Molecular Endocrinology (Baltimore, Md.)
|December 20, 2008
PubMed

Insights

Insulin-like growth factor-binding protein-2 (IGFBP-2) promotes prostate cancer growth by interacting with PAPA-1. This interaction inhibits IGFBP-2

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • Insulin-like growth factor-binding proteins (IGFBPs) mediate cellular effects through IGF-dependent and -independent pathways.
  • IGFBP-2 plays a role in regulating normal and cancerous cell growth, particularly in prostate cancer.
  • Understanding intracellular interactions of IGFBP-2 is crucial for elucidating its role in cancer progression.

Purpose of the Study:

  • To identify intracellular proteins that bind to IGFBP-2 using a yeast two-hybrid screen.
  • To investigate the functional consequences of the IGFBP-2 and PAPA-1 interaction on prostate cancer cell growth.
  • To explore the regulatory relationship between IGFBP-2, PAPA-1, and androgens in prostate cancer.

Main Methods:

  • Yeast two-hybrid screening of a human prostate cDNA library to identify IGFBP-2 interacting partners.
  • Coimmunoprecipitation and glutathione S-transferase pull-down assays to confirm in vitro protein interactions.
  • Confocal microscopy for subcellular localization studies, small interfering RNA (siRNA) for gene silencing, and cell proliferation assays (e.g., bromodeoxyuridine incorporation) in cell lines and mouse embryonic fibroblasts (MEFs).

Main Results:

  • Pim-1-associated protein-1 (PAPA-1) was identified as an intracellular binding partner of IGFBP-2.
  • IGFBP-2 and PAPA-1 colocalize in the nucleus, and their expression/localization are modulated by androgens.
  • Suppression of PAPA-1 enhanced IGFBP-2's growth-promoting effects, while PAPA-1 overexpression abrogated IGFBP-2-mediated proliferation in both LNCaP cells and IGFBP-2 knockout MEFs.

Conclusions:

  • The intracellular interaction between IGFBP-2 and PAPA-1 is a key mechanism regulating prostate cancer cell growth.
  • PAPA-1 acts as an inhibitor of IGFBP-2's growth-promoting function in prostate cancer.
  • Targeting the IGFBP-2/PAPA-1 interaction could represent a novel therapeutic strategy for prostate cancer.

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