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RAV12 Accelerates the Desensitization of Akt/PKB Pathway of Insulin-like Growth Factor I Receptor Signaling in COLO205

Raven Biotechnologies, Inc., South San Francisco, California

Requests for reprints: Jonathan Chi-Hang Li, Raven Biotechnologies, Inc., 1 Corporate Drive, South San Francisco, CA 94080. Phone: 650-624-2611; Fax: 650-553-9169; E-mail: jchl{at}ravenbio.com.

RAV12 is a high-affinity immunoglobulin G₁ (IgG₁) 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. [Cancer Res 2007;67(18):8856–64]