Growth Factors And Prostate Cancer

The insulin-like growth factor (IGF) system has been shown to play an important role in proliferation and differentiation of tissues. IGF promotes cancer cell growth in an autocrine/ paracrine manner via the IGF-1 receptor. It has also been implicated in the process of transformation to human epithelial prostate carcinoma. Recent studies suggest that there is a strong association between serum IGF-1 levels and prostate carcinoma, and that this growth factor may even be an important predictor of risk for prostate cancer.43,44 These growth factors activate their corresponding receptors leading to phosphorylation of second-messenger signaling systems and initiation of their individual downstream effects.

Insulin-like growth factor

IGF-I has been demonstrated to induce apoptotic resistance in various cell types following serum and interleukin-3 withdrawal, etoposide, adriamycin and anoikis-induced apoptosis.45 Its molecular effects on prostate cancer cells have yet to be determined. However, hormone manipulation induces the expression of insulin-like growth factor binding protein (IGFBP)-2, 3, 4 and 5, which can sequester away free IGF-I. IGF-I is known to act downstream of the c-myc oncogene and so block entry into the apoptotic pathway.46 c-myc expression is raised after castration and, therefore, IGF-I may abrogate castration-induced apoptosis.46 In other cell types, IGF-I stimulates the expression of Bcl-2, Bcl-X and Mcl-1.47 Overexpression or up-regulation of Bcl-2 occurs 2-3 months after androgen ablation. Current work in our laboratory has demonstrated that IGF-I does induce expression of Bcl-X and Mcl-1 in PC-3 and LNCaP prostatic cell lines, thereby inducing a resistance to both chemical and radiation induced apoptosis. Our work supports the theory that IGF-I may be involved in the progression or development of prostate cancer, in particular androgen independence. How IGF-1 signals for this response may have more important implications in the regulation of prostate cancer resistance to apoptosis.

Ligation of the IGF-1 receptor activates an intracellular tyrosine kinase domain, resulting in phosphorylation of several substrates. Two important intracellular signal transduction pathways are known to be activated, namely the Ras mitogen-activated protein kinase (MAP kinase) pathway and the phos-phatidylinositol 3-kinase (PI3K)/Akt pathway.45 Activation of Ras induces an increase in MAP kinase activity, resulting in protein expression. Activation of PI3K stimulates Akt kinase activity, resulting in the phosphorylation of proteins including Bad, a pro-apoptotic protein. PI3K is also known to phosphor-ylate focal adhesion kinase (FAK) involved in cell adhesion signaling.45

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