p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma

Abstract

p75NTR, a member of TNF receptor family, is the low affinity receptor common to several mature neurotrophins and the high affinity receptor for pro-neurotrophins. Brain-Derived Neurotrophic Factor (BDNF), a member of neurotrophin family has been described to play an important role in development and progression of several cancers, through its binding to a high affinity tyrosine kinase receptor B (TrkB) and/or p75NTR. However, the functions of these two receptors in renal cell carcinoma (RCC) have never been investigated. An overexpression of p75NTR, pro-BDNF, and to a lesser extent for TrkB and sortilin, was detected by immunohistochemistry in a cohort of 83 clear cell RCC tumors. p75NTR, mainly expressed in tumor tissues, was significantly associated with higher Fuhrman grade in multivariate analysis. In two derived-RCC lines, 786-O and ACHN cells, we demonstrated that pro-BDNF induced cell survival and migration, through p75NTR as provided by p75NTR RNA silencing or blocking anti-p75NTR antibody. This mechanism is independent of TrkB activation as demonstrated by k252a, a tyrosine kinase inhibitor for Trk neurotrophin receptors. Taken together, these data highlight for the first time an important role for p75NTR in renal cancer and indicate a putative novel target therapy in RCC.

MicroRNA-107 inhibits tumor growth and metastasis by targeting the BDNF-mediated PI3K/AKT pathway in human non-small lung cancer

“…Binding of BDNF to its major receptor, tropomyosin-related receptor kinase B (TrkB) with high affinity and specificity ( 27 ), caused the activation of multiple downstream signaling pathway, such as PI3K/AKT, RAS/ERK, PLC/PKC, AMPK/ACC and JAK/STAT pathways ( 28 ). Recently studies have demonstrated that BDNF was able to promote tumorigenesis and progression in several human malignancies, such as clear cell renal cell carcinoma ( 29 ), breast ( 30 ), colon cancer ( 31 ), colorectal cancer ( 32 ), and neuroblastoma ( 33 ), suggesting that BDNF was closely associated with tumor progression. For NSCLC, It was reported that the expression of BDNF was upregulated in NSCLC tissues, and was associated with poor prognosis in non-small cell lung cancer ( 34 ), and that BDNF facilitates tumorigenesis of NSCLC ( 35 ), and NSCLC metastasis ( 36 ).…”

Neurotensin receptor type 2 protects B-cell chronic lymphocytic leukemia cells from apoptosis

“…Optimal concentrations of exogenous BDNF and NTS were determined previously. 14 , 21 The non-peptide NTSR antagonist SR142948A (Tocris Biosciences, Bristol, UK) was used at 67 n M , 56 PTX (Sigma-Aldrich, St Louis, MO, USA) at 200 ng/ml 35 , 57 ; TrkB inhibitors were K252a (Alomone Labs) at 100 n M 58 , 59 or ANA12 (Tocris Biosciences) at 100 μ M . 60 …”

Role of the nervous system in cancer metastasis

“…BDNF facilitates cancer metastasis via binding to its receptors, TrkB/ TrkC and/or p75NTR as demonstrated in breast [ 79 ], colorectal [ 80 , 81 ], clear cell renal cell carcinoma [ 82 ] and non-small cell lung cancer (NSCLC) [ 83 ]. The expression of TrkB associates with nodal metastasis and peritoneal metastasis; whereas, TrkC expression associates with liver metastasis in colorectal cancer patients [ 81 ].…”