Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro.
In the prostate, cellular growth and differentiation are finely regulated by a complex interaction between stromal and epithelial cells under the control of both autocrine and paracrine regulatory factors such as the nerve growth factor (NGF). However, the role of NGF and its receptors including the high-affinity p-140 TrkA and the low-affinity p75 NTR receptors remains controversial. Moreover prostate tissues stored other neutrophins such as NT3, NT4 and brain derived neutrophic factor (BDNF) as well as the corresponding receptors (NTRs). Different members of NTRs are expressed during prostate cancer (PCa) progression, suggesting their involvement in cell proliferation, anoikis protection and malignancy. Therefore, we analyzed the expression of NTRs including NTRK1 (TrkA), NTRK2 (TrkB), NTRK3 (TrkC) and p75 NGFR in a panel of 7 well-characterized PCa cell lines and 12 cell derivatives from PC3 (4), DU145 (2), CWR22R (4) and LnCap (2) cell lines possessing different proliferative/invasive capabilities. We evaluated also the role of NGF, BDNF and NT3 in the modulation of cell migration and invasion and, finally, the effects of a pan Trk inhibitor, CEP-701 which has been included in some clinical trials for the treatment of PCa. We observed the following: i) TrkA and TrkB expression was significantly higher in AR-negative compared to AR-positive cells; ii) TrkA and TrkB expression was related to the invasive capacity/malignancy of PCa cells; iii) p75 NGFR could be considered a tumor suppressor gene which is present at high levels only in AR-positive cells; and iv) that NGF and BDNF (targeting TrkA/p75 NTR and TrKB, respectively) induced cell migration and this was inhibited by the CEP-701 treatment. In conclusion, the malignancy of PCa seems to be accompanied by increased TrkA and TrkB signaling (with a reduction of p75 NGFR expression) and CEP-701 could be used to reduce the metastasis formation in advanced PCa. CEP-701 is a trademark of Cephalon Inc., West Chester, PA, USA.
Festuccia
Claudio
C
Department of Experimental Medicine, University of L'Aquila, I-67100 L'Aquila, Italy. festucci@univaq.it
Muzi
Paola
P
Gravina
Giovanni Luca
GL
Millimaggi
Danilo
D
Speca
Silvia
S
Dolo
Vincenza
V
Ricevuto
Enrico
E
Vicentini
Carlo
C
Bologna
Mauro
M
D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005663:Furans; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009361:Neoplasm Invasiveness; D009414:Nerve Growth Factors / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000235:genetics; D011944:Receptors, Androgen / Q000032:analysis
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005663:Furans; D007211:Indoles; D009414:Nerve Growth Factors; D011944:Receptors, Androgen; C119379:lestaurtinib; D011505:Protein-Tyrosine Kinases; D020917:Receptor, trkA