Wu Jennifer D, Haugk Kathy, Woodke Libby, Nelson Peter, Coleman Ilsa, Plymate Stephen R
Department of Medicine, University of Washington, Seattle, Washington, USA.
J Cell Biochem. 2006 Oct 1;99(2):392-401. doi: 10.1002/jcb.20929.
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.
胰岛素样生长因子I型受体（IGF-IR）被认为在前列腺癌进展中起重要作用，可能在向雄激素非依赖性（AI）疾病的进展中也起作用。术语“AI”可能并不完全准确，因为最近的数据表明雄激素受体（AR）和雄激素调节基因的表达是激素消融后与前列腺癌进展的主要关联。因此，在没有雄激素配体的情况下，通过其他生长因子的信号传导被认为在AR介导的前列腺癌向AI疾病的进展中起作用。然而，关于IGF-IR信号传导如何与前列腺癌中的AR激活相互作用的现有数据相互矛盾。在这篇前瞻性文章中，我们回顾了一些关于IGF-IR/AR相互作用机制的已发表数据，并提出了新的证据，即IGF-IR信号传导可能调节AR的区室化，从而改变前列腺癌细胞中的AR活性。抑制IGF-IR信号传导可导致AR在细胞质中滞留，并使雄激素调节的基因表达发生显著变化。AR从细胞质向细胞核的转位可能与IGF诱导的去磷酸化有关。由于靶向IGF-IR的全人源化抗体目前正在进行临床试验，本综述旨在揭示这些抗体对AI前列腺癌潜在治疗作用的机制。
