Abstract 4337: Interactions of brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) systems in neuroblastoma: New insight into mechanisms of BDNF's pro-survival effects

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-04, Vol.71 (8_Supplement), p.4337-4337
• Main Authors: Czarnecka, Magdalena K., Kuan-Celarier, Anna, Lu, Congyi, Everhart, Lindsay, Kitlinska, Joanna
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-4337

BDNF is a known survival factor for neuroblastomas (NB) and is implicated in the development of their chemoresistance. NPY, on the other hand, is a sympathetic neurotransmitter, which is highly released from NB tumors. The elevated NPY levels in NB patients are associated with poor clinical outcome, which is in agreement with its Y2 receptor (Y2R)-mediated proliferative effects on NB cells and pro-angiogenic activities. In normal sympathetic neurons, BDNF has been shown to up-regulate NPY expression, while NPY itself has been implicated in promoting their survival. Therefore, we sought to determine if similar interactions between BDNF and NPY systems occur in NB cells. We have found that BDNF up-regulates expression of both NPY and its Y2Rs in native NB cells, as well as SH-SY5Y cells transfected with BDNF receptor – TrkB (SH-SY5Y/TrkB). However, even more dramatically, BDNF induces expression of another NPY receptor – Y5R, which is not detectable in most NB cell lines under basal conditions. In agreement with this, expression of Y5Rs correlated with TrkB and BDNF expression in human NB samples. In addition, Y5R seems to be directly involved in BDNF signaling. In SH-SY5Y/TrkB cells, BDNF-induced activation of p44/42 MAPK is significantly reduced by selective Y5R antagonist, CGP 71683, but not by Y2R antagonist, BIIE 0246. Interestingly, the Y5R antagonist had no effect on Akt activation stimulated by BDNF. Thus, these data suggest specific cross-talk between TrkB and Y5R signaling leading to activation of p44/42 MAPK pathway. Since BDNF is a known survival factor for NB cells, we sought to determine if pro-survival activity of BDNF is mediated by NPY. Chemotherapy was found to up-regulate the expression of both BDNF and NPY systems. This was further supported by elevated expression of NPY and its Y5Rs in cells derived from a chemotherapy-treated patient (CHLA-20, SMS-KANR) as compared to cells derived from primary tumors of the same patient (CHLA-15, SMS-KAN). In the functional studies, NPY mimicked the anti-apoptotic effect of BDNF in chemotherapy-treated NB cells. Moreover, as observed with MAPK activation, blocking Y5Rs, but not Y2Rs, reduced the pro-survival activity of BDNF in these cells. In summary, while Y2R is the main NPY R constitutively expressed in NBs and responsible for its proliferative effect, expression of Y5R is induced by BDNF and chemotherapy, subsequently enhancing the pro-survival functions of NPY. These anti-apoptotic actions of NPY