Fine-Tuning Roles of Endogenous Brain-Derived Neurotrophic Factor, TrkB and Sortilin in Colorectal Cancer Cell Survival

Akil, Hussein; Perraud, Aurélie; Mélin, Carole; Jauberteau, Marie‐Odile; Mathonnet, Muriel

doi:10.1371/journal.pone.0025097

Cited by 79 publications

(98 citation statements)

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“…In our recent study, the proBDNF/p75NTR pathway appeared to inhibit malignant glioma cell growth and migration (13). A recent report also showed that proBDNF suppressed the growth of colorectal cancer cells (14). Therefore, we postulated that the mature form of BDNF plays a supportive role in the growth and migration of tumour cells.…”

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confidence: 71%

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Mature BDNF promotes the growth of glioma cells in vitro

et al. 2013

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Abstract. High-grade glioma is incurable and is associated with a short survival time and a poor prognosis. There are two forms of brain-derived neurotrophic factor (BDNF), proBDNF and mature BDNF, which exert opposite effects. Their diverse actions are mediated through two different transmembrane receptor signalling systems: p75NTR and TrkB. The important roles of the BDNF/TrkB signalling system in tumour cell proliferation and survival have been demonstrated. However, few studies have been able to distinguish mature BDNF from proBDNF due to the limitation of specific antibodies. Using specific proBDNF antibodies, we demonstrated that the proBDNF/p75NTR pathway appears to inhibit malignant glioma cell growth and migration. In the present study using specific mature BDNF antibodies, we found that mature BDNF inhibited C6 glioma cell apoptosis and increased cell growth and migration in vitro. Our data suggest that the counterbalance between mature BDNF and proBDNF may regulate tumour growth. IntroductionBrain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is known to regulate cell growth, differentiation, migration and apoptosis in the nervous system (1,2). There are two forms of BDNF, a precursor and a mature form, in the central nervous system (CNS) (3). The precursor of BDNF (proBDNF) is synthesised and subsequently cleaved either intracellularly by prohormone convertases (PCs) and/ or furin, or extracellularly by plasmin and matrix metalloproteases (MMPs) to release the mature homodimeric protein (mature BDNF) (4,5). Their diverse actions are mediated through two different transmembrane receptor signalling systems: Trk tyrosine kinase B (TrkB) receptor and p75 neurotrophin receptor (NTR). Mature BDNF activates the high affinity TrkB receptor, promoting cell survival while proBDNF binds to both p75NTR and the co-receptor sortilin with a high affinity, to modulate cell apoptosis (6-8).Increasing evidence suggests that altered signalling through TrkB promotes tumour formation and metastasis. TrkB, in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, where it may allow tumour expansion and contribute to resistance to antitumour agents (9). Neurotrophin genes were found to be expressed in 24 cell lines derived from human malignant gliomas, and the BDNF gene was most abundantly expressed (10). Expression of Trk receptors (TrkA, TrkB and TrkC) has been detected in human astrocytomas and promotes tumour growth. Furthermore, activation of the JNK pathway may contribute to progression towards malignancy (11). Expression of BDNF and TrkB is also observed in human gangliogliomas (12). However, histological data in previous studies were unable to distinguish mature BDNF from proBDNF due to the lack of specific antibodies. We generated specific antibodies to mature BDNF and proBDNF, respectively. In our recent study, the proBDNF/p75NTR pathway appeared to inhibit malignant glioma cell gr...

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confidence: 71%

“…However, few studies were able to distinguish mature BDNF from proBDNF due to the limitation of specific antibodies. Recent studies have shown that proBDNF is a potent tumour suppressor (13,14). We previously generated specific antibodies to mature BDNF and proBDNF, respectively.…”

Section: Discussionmentioning

confidence: 99%

Mature BDNF promotes the growth of glioma cells in vitro

et al. 2013

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“…Neurotrophins are overexpressed in cancer (77) and implicated in neurodegeneration and inflammation (78). Sortilin binds via the C terminus of progranulin, suggesting that the C-terminal granulin domain can potentially mediate the binding even after proteolytic cleavage.…”

Section: What Is the Progranulin Receptor?mentioning

confidence: 99%

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Sephton

Cenik

Herz

et al. 2012

Journal of Biological Chemistry

203

196

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GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration. Progranulin: The BasicsProgranulin (encoded by GRN) is widely expressed in epithelia, bone marrow, immune cells, solid organs, and the nervous system both during development and in adulthood (1-5). In the brain, intracellular expression is highest in neurons and activated microglia (6 -8). At the subcellular level, progranulin colocalizes with the endoplasmic reticulum and Golgi markers in the secretory pathway and the lysosomal marker Lamp1 (9, 10). Progranulin is a secreted glycoprotein and is readily detected in blood and cerebrospinal fluid (11)(12)(13).Progranulin is evolutionarily conserved in Animalia: homologs exist in vertebrates and Caenorhabditis elegans (14), but seemingly not in Drosophila. It has no robust sequence homology to any other known protein family. Biological activities attributed to progranulin are numerous; the protein is made up of several granulin domains, which can be individually liberated by neutrophil proteases (see Fig. 1). These "granulins" were discovered first, before the cloning of the full-length gene. Whether the biological activities of progranulin are mediated by the full-length protein, individual granulins, or both is not clear. We begin our discussion with the consequences of progranulin deficiency. Progranulin Haploinsufficiency Causes Frontotemporal Lobar Degeneration with Ubiquitinated TDP-43-positive InclusionsIn 2006, mutations in GRN were discovered to be a cause of frontotemporal lobar degeneration (FTLD) 3 with ubiquitinated TDP-43-positive inclusions (FTLD-TDP) (15,16). FTLD is the second most common presenile dementia disorder after Alzheimer disease, representing 5-15% of all dementias (17,18). More than 70 mutations in GRN, almost all of which result in null alleles, have been identified in FTLD patients. A few causative missense mutations also result in reduced levels of progranulin (19).Clinical manifestations of heterozygous loss-of-function GRN mutations include variants of the FTLD spectrum, parkinsonism, and the corticobasal syndrome (20). Neuropathologically, atrophy of the brain parenchyma (most severe in the frontal cortex) is usually observed. The atrophy can be asymmetrical, and different brain regions are affected with varying frequency. Loss of pigmentation of the substantia nigra, hippocam...

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“…Increased BDNF and TrkB expressions have recently been found in several human tumors (13)(14)(15). BDNF/TrkB promote cancer cell survival and resistance to chemotherapy, while small-molecule inhibitors of Trk, such as K252α, inhibit cell growth and induce apoptotic death in cancer cells (16)(17)(18)(19). TrkB expression has been described in ovarian and cervical cancers (20,21), while being associated with a shorter survival and the promotion of metastasis in ovarian cancer patients (20 in cell proliferation, migration and suppression of anoikis (22,23).…”

Section: Introductionmentioning

confidence: 99%

Influence of GRPR and BDNF/TrkB signaling on the viability of breast and gynecologic cancer cells

Cornélio

Farias

Prusch

et al. 2012

Molecular and Clinical Oncology

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Abstract. Neuropeptide and neurotrophin receptors are increasingly important molecular targets in cancer. Scientific findings indicate that compounds blocking gastrin-releasing peptide receptors (GRPR) or tropomyosin receptor kinase (Trk) receptors are likely to have antiproliferative activities against cancer cells. The present study aimed to demonstrate that, in contrast to previous findings, GRPR activation reduces, whereas its blockade increases the viability of breast, ovarian and cervical cancer cell lines. However, consistent with previous studies, Trk inhibition was demonstrated to reduce the viability of these cells. MCF-7 (breast), OVCAR-3 (ovarian) and HeLa (cervical) human cancer cell lines were treated with GRP, the GRPR antagonists RC-3095 and RC-3940-II, brain-derived neurotrophic factor (BDNF) and the Trk antagonist K252α. Cell viability was measured by the MTT assay. Expression of GRPR and BDNF was confirmed with reverse transcription-polymerase chain reaction (RT-PCR). GRP reduced, whereas RC-3940-II enhanced the viability of the three cell lines. Treatment with K252α inhibited the viability of the cell lines, while BDNF increased the viability of OVCAR-3 cells. The results supported the hypothesis that GRPR and BDNF/TrkB signaling regulates cancer cell viability. Most importantly, these findings are the first to demonstrate that GRPR blockade can stimulate, rather than inhibits the viability of breast and gynecologic cancer cell lines.

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Fine-Tuning Roles of Endogenous Brain-Derived Neurotrophic Factor, TrkB and Sortilin in Colorectal Cancer Cell Survival

Cited by 79 publications

References 64 publications

Mature BDNF promotes the growth of glioma cells in vitro

Mature BDNF promotes the growth of glioma cells in vitro

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Influence of GRPR and BDNF/TrkB signaling on the viability of breast and gynecologic cancer cells

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