In vitro downregulation of growth factors by insulin-like growth factor binding protein-3 in cervical cancer.
OBJECTIVE
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.
Mathur
Rajesh S
RS
Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC 29425, USA. mathurs@musc.edu
Mathur
Subbi P
SP
D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000096:biosynthesis / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
D018972:Insulin-Like Growth Factor Binding Protein 3; D042461:Vascular Endothelial Growth Factor A; D007335:Insulin-Like Growth Factor II; D005492:Folic Acid; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1