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Updated: Jul 18, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Phosphorylation by DNA-dependent protein kinase is critical for apoptosis induction by insulin-like growth factor

Laura J Cobb1, Bingrong Liu, Kuk-Wha Lee

  • 1Division of Pediatric Endocrinology, Mattel Children's Hospital at University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Cancer Research
|November 17, 2006
PubMed

Insights

Insulin-like growth factor binding protein-3 (IGFBP-3) requires DNA-dependent protein kinase (DNA-PK) activity to promote cancer cell apoptosis. Phosphorylation at Serine 156 by DNA-PK is critical for IGFBP-3

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Insulin-like growth factor binding protein-3 (IGFBP-3) induces cancer cell apoptosis via IGF-dependent and -independent pathways.
  • DNA-dependent protein kinase (DNA-PK) can phosphorylate IGFBP-3 in vitro, but its functional significance remains unclear.

Purpose of the Study:

  • To investigate the functional role of DNA-PK in mediating the anti-cancer effects of IGFBP-3.
  • To identify specific phosphorylation sites on IGFBP-3 critical for its activity.

Main Methods:

  • Utilized a DNA-PK chemical inhibitor in prostate cancer cells.
  • Employed glioblastoma cell lines with and without DNA-PK expression.
  • Performed site-directed mutagenesis on potential DNA-PK phosphorylation sites in IGFBP-3.

Main Results:

  • IGFBP-3's apoptosis-promoting and growth-inhibitory effects were abolished without active DNA-PK.
  • IGFBP-3 showed reduced nuclear accumulation and impaired retinoid X receptor alpha (RXRα) binding in the absence of DNA-PK activity.
  • Mutating Serine 156 (IGFBP-3-S156A) abrogated apoptosis promotion and reduced nuclear localization, unlike mutations at Serine 165 or Threonine 170.

Conclusions:

  • DNA-PK activity is essential for IGFBP-3's pro-apoptotic and anti-proliferative functions in cancer cells.
  • Phosphorylation of IGFBP-3 by DNA-PK, particularly at Serine 156, is a key regulatory mechanism for its nuclear actions and anti-cancer effects.
  • This identifies a novel pathway for regulating IGFBP-3 activity in prostate cancer treatment strategies.

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