Insulin-like growth factor 2 expression modulates taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer

Gloria S. Huang, Jurriaan Brouwer-Visser, Marissa J. Ramirez, Christine H. Kim, Tiffany M. Hebert, Juan Lin, Hugo Arias-Pulido, Clifford R. Qualls, Eric R. Prossnitz, Gary L. Goldberg, Harriet O. Smith, Susan Band Horwitz

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Purpose: This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors. Experimental Design: The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phospho-AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. A type 1 IGF receptor (IGF1R) inhibitor, NVP-AEW541, and IGF2 small interfering RNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors and analyzed in relation to clinical/pathologic factors using the χ2 or Fisher's exact tests. The influence of IGF2 expression on survival was studied with Cox regression. Results: Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (P < 0.001) and tumor grade (P < 0.01) and reduced disease-free survival (P < 0.05). Conclusions: IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance.

Original languageEnglish (US)
Pages (from-to)2999-3010
Number of pages12
JournalClinical Cancer Research
Volume16
Issue number11
DOIs
StatePublished - Jun 1 2010

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Somatomedins
Paclitaxel
Ovarian Neoplasms
Disease-Free Survival
Biomarkers
Neoplasms
Carcinoma
Phospho-Specific Antibodies
IGF Type 1 Receptor
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Research Design
Up-Regulation
Immunohistochemistry
Phosphorylation
Phenotype
Cell Line
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Insulin-like growth factor 2 expression modulates taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer. / Huang, Gloria S.; Brouwer-Visser, Jurriaan; Ramirez, Marissa J.; Kim, Christine H.; Hebert, Tiffany M.; Lin, Juan; Arias-Pulido, Hugo; Qualls, Clifford R.; Prossnitz, Eric R.; Goldberg, Gary L.; Smith, Harriet O.; Band Horwitz, Susan.

In: Clinical Cancer Research, Vol. 16, No. 11, 01.06.2010, p. 2999-3010.

Research output: Contribution to journalArticle

Huang, Gloria S. ; Brouwer-Visser, Jurriaan ; Ramirez, Marissa J. ; Kim, Christine H. ; Hebert, Tiffany M. ; Lin, Juan ; Arias-Pulido, Hugo ; Qualls, Clifford R. ; Prossnitz, Eric R. ; Goldberg, Gary L. ; Smith, Harriet O. ; Band Horwitz, Susan. / Insulin-like growth factor 2 expression modulates taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 11. pp. 2999-3010.
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abstract = "Purpose: This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors. Experimental Design: The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phospho-AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. A type 1 IGF receptor (IGF1R) inhibitor, NVP-AEW541, and IGF2 small interfering RNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors and analyzed in relation to clinical/pathologic factors using the χ2 or Fisher's exact tests. The influence of IGF2 expression on survival was studied with Cox regression. Results: Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (P < 0.001) and tumor grade (P < 0.01) and reduced disease-free survival (P < 0.05). Conclusions: IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance.",
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T1 - Insulin-like growth factor 2 expression modulates taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer

AU - Huang, Gloria S.

AU - Brouwer-Visser, Jurriaan

AU - Ramirez, Marissa J.

AU - Kim, Christine H.

AU - Hebert, Tiffany M.

AU - Lin, Juan

AU - Arias-Pulido, Hugo

AU - Qualls, Clifford R.

AU - Prossnitz, Eric R.

AU - Goldberg, Gary L.

AU - Smith, Harriet O.

AU - Band Horwitz, Susan

PY - 2010/6/1

Y1 - 2010/6/1

N2 - Purpose: This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors. Experimental Design: The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phospho-AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. A type 1 IGF receptor (IGF1R) inhibitor, NVP-AEW541, and IGF2 small interfering RNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors and analyzed in relation to clinical/pathologic factors using the χ2 or Fisher's exact tests. The influence of IGF2 expression on survival was studied with Cox regression. Results: Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (P < 0.001) and tumor grade (P < 0.01) and reduced disease-free survival (P < 0.05). Conclusions: IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance.

AB - Purpose: This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors. Experimental Design: The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phospho-AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. A type 1 IGF receptor (IGF1R) inhibitor, NVP-AEW541, and IGF2 small interfering RNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors and analyzed in relation to clinical/pathologic factors using the χ2 or Fisher's exact tests. The influence of IGF2 expression on survival was studied with Cox regression. Results: Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (P < 0.001) and tumor grade (P < 0.01) and reduced disease-free survival (P < 0.05). Conclusions: IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance.

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