Heterodimerization of Glycosylated Insulin-Like Growth Factor-1Receptors and Insulin Receptors in Cancer Cells Sensitive to Anti-IGF1RAntibody

Collection with item attached
2012
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/479810.do
DOI
10.1371/journal.pone.0033322
Title
Heterodimerization of Glycosylated Insulin-Like Growth Factor-1Receptors and Insulin Receptors in Cancer Cells Sensitive to Anti-IGF1RAntibody
Description
This study was partially funded by the Korean healthcare 21 andtechnology R&D project, Ministry for Health, Welfare & Family Affairs,Republic of Korea (A091081), and supported by grant No.R31-2008-000-10103-0 from the World Class University program of the MESTand the NRF. The funders had no role in study design, data collectionand analysis, decision to publish, or preparation of the manuscript.
abstract
Background: Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulinlike 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.
provenance
Made available in Cube on 2018-09-28T13:09:21Z (GMT). No. of bitstreams: 0
language
English
author
Kim, Jun Gyu
Kang, Min Jueng
Yoon, Young-Kwang
Kim, Hwang-Phill
Park, Jinah
Song, Sang-Hyun
Han, Sae-Won
Park, Jong-Wan
Kang, Gyeong Hoon
Kang, Keon Wook
Oh, Do Youn
Im, Seock-Ah
Bang, Yung-Jue
Yi, Eugene C.
Kim, Tae-You
orcid
Kang, Keon Wook/0000-0003-2622-9017; Kang, Gyeong
Hoon/0000-0003-2380-6675
accessioned
2018-09-28T13:09:21Z
available
2018-09-28T13:09:21Z
issued
2012
citation
PLOS ONE(7): 3
issn
1932-6203
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/479810.do
Funder
교육과학기술부
Funding Program
세계수준의연구중심대학육성_일반(0.5)
Project ID
1345196339
Jurisdiction
Rep.of Korea
Project Name
Integrated Research on Molecular Medicine and Biopharmaceutical Sciences
rights
openAccess
type
article


Files in This Item

There are no attached files.