Abstract
RAV12 is a high-affinity immunoglobulin G(1) (IgG(1)) chimeric antibody recognizing an N-linked carbohydrate epitope expressed on a number of human carcinomas and adenocarcinomas. RAV12 is efficacious in treating colon, gastric, and pancreatic tumors in xenograft models in vivo. Insulin-like growth factor-I receptor (IGF-IR) is a protein widely overexpressed in tumor-derived cell lines that promotes cell survival and prevents apoptosis. We found the RAV12 epitope (RAAG12) decorated the IGF-IR proteins of RAV12-responsive cell lines such as COLO201, COLO205, and SNU-16. Here, we report findings of IGF-IR signaling manipulation by RAV12. We found that RAV12 caused a significantly accelerated IGF-I-mediated IGF-IR phosphorylation and desensitization in COLO205. We also observed significant changes in some of the major downstream signaling components of IGF-IR. Data suggested that RAV12 treatment accelerated the desensitization of Akt/PKB through IRS1, and such activation could be attenuated by Tyrphostin AG538 (IGF-IR inhibitor), LY294002, or Wortmannin (phosphoinositide-3-kinase inhibitor). Furthermore, RAV12-inhibited IGF-I stimulated COLO205 growth, and the inhibition could be significantly augmented by mitogen-activated protein kinase inhibitor.
Highlights
Research on cell signaling in cancer biology has provided invaluable information supporting the development of antibodybased therapy
Data suggested that RAV12 treatment accelerated the desensitization of Akt/PKB through IRS1, and such activation could be attenuated by Tyrphostin AG538 (IGF-IR inhibitor), LY294002, or Wortmannin
Given the existence of epidermal growth factor receptor (EGFR)/insulin-like growth factor-IR (IGF-IR) crosstalk [3, 4], the dependence of EGFR on IGF-IR pathway [5, 6] and the role of IGF-I/IGF-IR signaling in regulating cell transformation, tumorigenesis, and apoptosis [7, 8], IGF-IR may be a target for future therapeutic development [9, 10]
Summary
Research on cell signaling in cancer biology has provided invaluable information supporting the development of antibodybased therapy. For IGF-IR phosphorylation kinetic studies, serum-starved COLO205 were pretreated with 50 Ag/mL RAV12 or serum-free F12/DMEM at 37jC for 4 h. COLO205 were serum starved, pretreated with RAV12 or serum-free F12/DMEM, washed, and post-stimulated with IGF-I as described in IGF-IR phosphorylation kinetic studies.
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