In vitro downregulation of growth factors by insulin-like growth factor binding protein-3 in cervical cancer

Gynecol Oncol. 2003 Nov;91(2):410-5. doi: 10.1016/s0090-8258(03)00513-4.


Objectives: Our hypothesis is that insulin-like growth factor binding protein 3 (IGF-BP3) would downregulate epidermal growth factor receptor (EGF-R) levels in cervical cancer cell lines, thereby reducing cellular IGF-II and angiogenesis-related vascular endothelial cell growth factor (VEGF). As folate deficiency is a risk factor in cervical cancer, we sought to determine if folic acid treatment might increase IGF-BP3 production, thereby inhibiting malignant cell proliferation.

Methods: We determined the cellular levels of EGF-R, IGF-II, and VEGF in the cervical cancer cell lines HeLa, ME-180 (both positive for human papilloma virus; HPV), and HT-3 (HPV-negative), following their treatment with IGF-BP3. Levels of IGF-BP3 in these cells before and after treatment with folic acid and VEGF were also enumerated, using a computerized semiquantitative immunofluorescent antibody assay.

Results: Treatment with IGF-BP3 significantly reduced the levels (mean intensity per pixel) of EGF-R, IGF-II, and VEGF in all three cell lines and IGF-I receptor (IGF-IR) in representative ME-180 cell line. Treatment with antiproliferative folic acid increased IGF-BP3 levels while the proliferative VEGF depleted cellular IGF-BP3 in all the cell lines.

Conclusions: Levels of EGF-R, IGF-II, IGF-IR, and VEGF are significantly reduced following treatment with IGF-BP3 in cervical cancer. We observed increased levels of IGF-BP3 by folic acid, and decreased IGF-BP3 levels by VEGF. Downregulation of EGF-R by IGF-BP3 suggests an IGF-independent action. Folate deficiency is a risk factor in cervical cancer. Our results suggest that folic acid supplementation can lead to inhibition of cervical cancer cell growth by promoting increased IGF-BP3 levels.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / drug effects
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • ErbB Receptors / biosynthesis*
  • ErbB Receptors / genetics
  • Female
  • Folic Acid / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / biosynthesis
  • Insulin-Like Growth Factor Binding Protein 3 / pharmacology*
  • Insulin-Like Growth Factor II / biosynthesis*
  • Insulin-Like Growth Factor II / genetics
  • Receptor, IGF Type 1 / biosynthesis
  • Receptor, IGF Type 1 / genetics
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / pathology
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Vascular Endothelial Growth Factor A / genetics


  • Insulin-Like Growth Factor Binding Protein 3
  • Vascular Endothelial Growth Factor A
  • Insulin-Like Growth Factor II
  • Folic Acid
  • ErbB Receptors
  • Receptor, IGF Type 1