Abstract 2924: IGF-IR inibition induces MAPK signaling in prostate carcinoma cells

Abstract

Abstract Prostate carcinoma, the most common malignancy in men, metastasizes primarily to bone. Multiple factors, including integrins, chemokines, and growth factors are implicated in the regulation of this process. In our laboratory, we are interested in the role of the insulin-like growth factor (IGF) family of proteins in the regulation of tumor metastasis to bone. Metastatic prostate carcinoma cells express the type I IGF receptor (IGF-IR) and are responsive to IGF ligands. Therefore, it has been suggested that inhibitors against the IGF-IR may be effective against prostate carcinoma bone metastasis. Our hypothesis is that IGF-IR inhibitors will prevent prostate carcinoma growth and survival signaling. PC-3, LNCaP, and bone-adapted C42B prostate carcinoma cells were plated in a 96-well growth assay and treated with/without IGF-I and/or neutralizing antibody against the IGF-IR. Predictably, IGF-I treatment leads to an increase in cell number over a period of 4 d; however, inhibition of the IGF-IR enhances, rather than diminishes, this effect on growth. To further understand this paradoxical finding, Western immunoblotting was performed to analyze the effect of IGF-IR inhibition on IGF-IR expression and signaling. PC-3 cells were treated with increasing concentrations of a neutralizing antibody against the IGF-IR. With increasing concentrations of the neutralizing antibody, IGF-IR and Akt expression levels remain unchanged. In contrast, p44/p42 MAPK expression and activation increases with increasing concentrations of the IGF-IR neutralizing antibody. These data suggest that IGF-IR inhibition induces an upregulation of the p44/p42 MAPK pathway in PC-3 prostate carcinoma cells. The data collected indicate that our original hypothesis was incorrect. Our current hypothesis is that treatment of prostate carcinoma cells with the IGF-IR neutralizing antibody induces receptor internalization supporting prolonged signaling rather than lysosomal degradation. We are currently investigating this hypothesis using immunofluorescence and confocal microscopy.This work was supported by NIH/NCRR 2 P20 RR016472-09 (INBRE) and the Children's Neuroblastoma Cancer Foundation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2924. doi:10.1158/1538-7445.AM2011-2924