Heterodimerization of glycosylated insulin-like growth factor-1 receptors and insulin receptors in cancer cells sensitive to anti-IGF1R antibody.

Abstract

BACKGROUND:

Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer.

METHODOLOGY/PRINCIPAL FINDINGS:

In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity.

CONCLUSION AND SIGNIFICANCE:

The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells.

• Authors: Jun Gyu Kim, Min Jueng Kang, Young-Kwang Yoon, Hwang-Phill Kim, Jinah Park, Sang-Hyun Song, Sae-Won Han, Jong-Wan Park, Gyeong Hoon Kang, Keon Wook Kang, Do Youn Oh, Seock-Ah Im, Yung-Jue Bang, Eugene C Yi, Tae-You Kim
• Journal: PloS one (PLoS One) Vol. 7 Issue 3 Pg. e33322 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22438913 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Immunoglobulins, Intravenous
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• Receptor, IGF Type 1
• Receptor, Insulin
• Proto-Oncogene Proteins c-akt
• figitumumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Base Sequence
• Carcinoma, Hepatocellular (metabolism, pathology, therapy)
• Cell Division
• Cell Line, Tumor
• Dimerization
• Female
• G1 Phase Cell Cycle Checkpoints
• Gene Knockdown Techniques
• Glycosylation
• Hep G2 Cells
• Humans
• Immunoglobulins, Intravenous
• Liver Neoplasms (metabolism, pathology, therapy)
• Mice
• Mice, Inbred BALB C
• Protein Structure, Quaternary
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (genetics)
• Receptor, IGF Type 1 (antagonists & inhibitors, chemistry, genetics, metabolism)
• Receptor, Insulin (chemistry, metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction
• Stomach Neoplasms (metabolism, pathology, therapy)
• Xenograft Model Antitumor Assays