CROSS-TALK BETWEEN ANDROGEN RECEPTOR AND NERVE GROWTH FACTOR RECEPTOR IN PROSTATE CANCER CELLS: IMPLICATIONS FOR A NEW THERAPEUTIC APPROACH.

Nerve growth factor (NGF) is abundantly secreted by prostate cancer (PC) cells and However, the mechanism by which NGF signalling impinges on PC progression is still debated. In this report, we show that androgens and NGF both induce a reciprocal cross-talk between androgen receptor (AR) and tyrosine receptor kinase A (TrkA) in PC-derived LNCaP cells. The findings here collected point to the key role of this complex in promoting proliferation and motility of LNCaP cells upon challenging with androgens or NGF. Results obtained using the anti-androgen bicalutamide or GW441756, a specific inhibitor of TrkA, are in line with the idea that AR/TrkA cross-talk, now identified for the first time in PC cells, provides a rationale for interfering in PC progression through the use of combinatorial therapies, such as anti-androgens plus inhibitors of NGF receptor. Since androgen- or NGF-induced cell migration requires AR/filamin A association in various cell types, we also used the RH2025u stapled peptide, which specifically interrupts AR/filamin A complex assembly. At nanomolar concentration, the peptide inhibits LNCaP cell migration triggered by androgens or NGF, indicating that AR/filamin A complex is also utilized by NGF/TrkA axis to transmit motility signalling. In conclusion, we here report a novel link between extranuclear AR functions and PC progression, which relies on the receptor’s ability to intersect important signalling effectors or scaffolds, such as the NGF receptor or filamin A. In this context, the use of combinatorial therapies or new compounds selectively interfering in extranuclear AR functions might be envisaged when PC fails to respond to AR antagonists or tyrosine kinase inhibitors, commonly employed as single drugs in PC therapy.