Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer

Jurriaan Brouwer-Visser, Jiyeon Lee, KellyAnne McCullagh, Maria J. Cossio, Yanhua Wang, Gloria S. Huang

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone.

Original languageEnglish (US)
Article numbere100165
JournalPLoS One
Volume9
Issue number6
DOIs
StatePublished - Jun 16 2014

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paclitaxel
ovarian neoplasms
somatomedins
Somatomedins
Paclitaxel
Ovarian Neoplasms
drugs
drug resistance
Drug Resistance
Pharmaceutical Preparations
cell lines
Cells
Cell Line
therapeutics
Messenger RNA
neoplasms
Maximum Tolerated Dose
Atlases
Excipients
Therapeutics

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer. / Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J.; Wang, Yanhua; Huang, Gloria S.

In: PLoS One, Vol. 9, No. 6, e100165, 16.06.2014.

Research output: Contribution to journalArticle

Brouwer-Visser, Jurriaan ; Lee, Jiyeon ; McCullagh, KellyAnne ; Cossio, Maria J. ; Wang, Yanhua ; Huang, Gloria S. / Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer. In: PLoS One. 2014 ; Vol. 9, No. 6.
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