Interaction of IGF signaling and the androgen receptor in prostate cancer progression.
The insulin-like growth factor type I receptor (IGF-IR) has been suggested to play an important role in prostate cancer progression and possibly in the progression to androgen-independent (AI) disease. The term AI may not be entirely correct, in that recent data suggest that expression of androgen receptor (AR) and androgen-regulated genes is the primary association with prostate cancer progression after hormone ablation. Therefore, signaling through other growth factors has been thought to play a role in AR-mediated prostate cancer progression to AI disease in the absence of androgen ligand. However, existing data on how IGF-IR signaling interacts with AR activation in prostate cancer are conflicting. In this Prospect article, we review some of the published data on the mechanisms of IGF-IR/AR interaction and present new evidence that IGF-IR signaling may modulate AR compartmentation and thus alter AR activity in prostate cancer cells. Inhibition of IGF-IR signaling can result in cytoplasmic AR retention and a significant change in androgen-regulated gene expression. Translocation of AR from the cytoplasm to the nucleus may be associated with IGF-induced dephosphorylation. Since fully humanized antibodies targeting the IGF-IR are now in clinical trials, the current review is intended to reveal the mechanisms of potential therapeutic effects of these antibodies on AI prostate cancers.
Wu
Jennifer D
JD
Department of Medicine, University of Washington, Seattle, Washington, USA.
Haugk
Kathy
K
Woodke
Libby
L
Nelson
Peter
P
Coleman
Ilsa
I
Plymate
Stephen R
SR
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002471:Cell Transformation, Neoplastic; D015870:Gene Expression; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D011471:Prostatic Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000628:therapy; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D014183:Transplantation, Heterologous
D018969:Insulin-Like Growth Factor Binding Proteins; D011944:Receptors, Androgen; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1