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NKX3.1 activates expression of insulin-like growth factor binding protein-3 to mediate insulin-like growth factor-I

Erin Muhlbradt1, Ekaterina Asatiani, Elizabeth Ortner

  • 1Lombardi Comprehensive Cancer Center, Washington, District of Columbia, USA.

Cancer Research
|March 5, 2009
PubMed

Insights

NKX3.1, a prostate cancer tumor suppressor, activates insulin-like growth factor binding protein-3 (IGFBP-3) expression. This activation mediates NKX3.1

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • NKX3.1 is a homeobox gene functioning as a prostate cancer tumor suppressor.
  • Reduced NKX3.1 protein levels are observed in most primary prostate cancer tissues.
  • NKX3.1's role in prostate cancer progression and its molecular targets require further elucidation.

Purpose of the Study:

  • To investigate the functional relationship between NKX3.1 and insulin-like growth factor binding protein-3 (IGFBP-3) in prostate cancer cells.
  • To determine the role of IGFBP-3 in mediating the growth-suppressive effects of NKX3.1.

Main Methods:

  • Utilized expression microarray analysis to assess mRNA expression changes.
  • Performed stable and transient transfections in PC-3 and LNCaP prostate cancer cell lines.
  • Investigated insulin-like growth factor-I (IGF-I) signaling pathways, including IGF-I receptor (IGF-IR) phosphorylation, using Western blotting and small interfering RNA (siRNA) knockdown.

Main Results:

  • NKX3.1 expression significantly increased IGFBP-3 mRNA and protein levels in prostate cancer cells.
  • NKX3.1 attenuated IGF-I-induced signaling through the IGF-IR pathway.
  • Knockdown of IGFBP-3 partially reversed NKX3.1's effects on IGF-IR signaling and abrogated NKX3.1's suppression of cell proliferation.

Conclusions:

  • NKX3.1 directly up-regulates IGFBP-3 expression both in vitro and in vivo.
  • NKX3.1 exerts its growth-suppressive effects in prostate cells, at least in part, through the induction of IGFBP-3.
  • The NKX3.1-IGFBP-3 axis represents a potential therapeutic target for prostate cancer.

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