Literature Review: Molecular Mechanism of Neuroendocrine Differentiation

Androgen receptor may actively repress the NE phenotype (Wright et al, 2003), providing an explanation for the emergence of the NE phenotype when AR signaling is inhibited, such as in hormonally-treated cancers or in LNCaP cells cultured in androgen-deprived media. Abrogation of FGF signaling by expression of a truncated FGFR2iiib receptor in prostatic epithelium of transgenic mice promotes NED (Foster et al, 2002). The same is observed in expression of a constitutively activated form of the heterotrimeric G-protein subunit alpha (Regnauld et al, 2002). Interaction of IGF-binding protein-related protein 1 with a novel protein, neuroendocrine differentiation factor, results in NED of prostate cancer cells (Wilson et al, 2001). Inhibition of COX-2, a proinflammatory enzyme, induces NF-kappa B and NED of LNCaP C4-2b subline (Meyer-Siegler, 2001). NED of LNCaP cells can be induced by agents increasing intracytoplasmic levels of cAMP (Cox et al, 1999), IL-6 or IL-1 (Albrecht et al, 2004). PKA signaling pathway may be important for NED (Cox et al, 2000). NED of LNCaP cells induced by heparin-binding epidermal growth factor-like growth factor (HB-EGF) involves mitogen-activated protein kinase (MAPK) signaling pathway (Kim et al, 2002). Papaverine combined with prostaglandin E2 (PGE2) synergistically induces NE differentiation of LNCaP cells (Shimizu et al, 2000). NED of LNCaP cells is accompanied by overexpression of an alpha 1H (Cav3.2) T-type calcium channel (Mariot et al, 2002) and changes in intracytoplasmic calcium homeostasis (Vanoverberghe et al, 2004). Protein tyrosine phosphatase alpha, a receptor type protein tyrosine phosphatatse, (Zelivianski et al, 2001; Zhang et al, 2003) and mAsh1, a basic helix-loop-helix (bHLH) transcription factor (Hu et al, 2004) may be involved in NED of prostate cancer cells. Silibinin, a flavonoid antioxidant, induces G1 arrest and NED of LNCaP cells through increasing Rb level, decreasing Rb phosphorylation and inhibition of key cell cycle regulators (Zi and Agarwal, 1999; Tyagi et al, 2002).

Recently, it has been demonstrated that neuroendocrine tumor cells in human prostate cancer tissue express interleukin-8 (Huang et al, 2005). IL-8 was initially identified as a regulator of leukocyte recruitment and trafficking (Onuffer JJ et al, 1992) but has also been found to be a mitogenic (Inoue et al, 2000) and angiogenic factor (Koch et al, 1992). In patients with PC, serum IL-8 levels increase with progression of the disease (Veltri et al, 1999, Lehrer et al, 2004). The PC cell line, PC3, expresses and secretes IL-8 (Moore et al, 1999) and also expresses the IL-8 receptor CXCR1 and CXCR2 (Reiland, 1999). PC cell line LNCaP does not express IL-8, but selection of the cells in androgen-deprived media led to the emergence of a cell line which produces IL-8 and is more tumorigenic than the parental cells (Patel et al , 2000). A recent study showed that IL-8 promotes androgen-independent growth and migration of LNCaP cells (Lee et al, 2004), suggesting that IL-8 may facilitate transition of PC to an androgen-independent state.

IL-6-induced NE differentiation involves the protein tyrosine kinase pathway (Chung et al, 2000; Qiu et al, 1998), members of the JAK-STAT family (Spiotto and Chung, 2000; 2000B), induction of cyclin-dependent kinase (CDK) inhibitor p27 (Kip1) and inhibition of CDKs (Mori et al, 1999). Androgen and androgen receptor can regulate IL-6-mediated LNCaP cell NED via directly modulating the IL-6-PI3-kinase pathway (Xie et al, 2004). Interestingly, IL-6-induced NED of LNCaP cells may be qualitatively different from that induced by agents such as epinephrine and forskolin which cause rapid but reversible NE differentiation of LNCaP cells by increasing intracellular concentrations of cAMP. The process of IL-6-induced NE differentiation takes more time and is permanent (Wang et al, 2004). In addition, the behavior of IL-6-treated cells may depend on the concentration of IL-6 used. Long-term exposure of LNCaP cells to low concentrations of IL-6 (5 ng/ml) results in the emergence of a LNCaP variant with more aggressive growth properties in vitro and in vivo (Hobisch et al, 2001; Steiner et al, 2003) while culture of LNCaP cells in high concentrations of IL-6 (100 ng/ml) for 2 weeks leads to permanent NED and significant loss of the proliferative potential (Wang et al, 2004). Therefore, even though NED is considered to promote progression of prostate cancer to androgen-independent state, it is possible that complete differentiation of cancer cells along the NE pathway may actually inhibit proliferation, providing a novel strategy for developing anti-prostate cancer therapy.

Literature Review Next Section: Summary and Conclusions

Back to top