RAV12 accelerates the desensitization of Akt/PKB pathway of insulin-like growth factor I receptor signaling in COLO205.
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.
Li
Jonathan Chi-Hang
JC
Raven Biotechnologies, Inc., South San Francisco, California 94080, USA. jchl@ravenbio.com
Li
Ronghao
R
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000628:therapy*; D019073:HT29 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007334:Insulin-Like Growth Factor I; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1