The Neurotrophic Receptor TrkB in Anoikis Resistance and Metastasis: A Perspective

Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Cancer Research (Impact Factor: 9.33). 09/2005; 65(16):7033-6. DOI: 10.1158/0008-5472.CAN-05-0709
Source: PubMed


Resistance to anoikis ("detachment-induced apoptosis") has been suggested to be a prerequisite for cancer cells to metastasize. In a functional screen for suppressors of anoikis, we identified the neurotrophic receptor TrkB. Upon s.c. inoculation in mice, TrkB-expressing cells formed highly invasive and metastatic tumors. Here, we discuss our findings within the context of the proposed role of TrkB in human malignancies and address the question of its feasibility as a target for cancer therapy.

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Available from: Thomas R Geiger, Jul 14, 2014
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    • "But increased cell death was observed in cells expressing Y289F PDHA1 compared with cells expressing WT PDHA1 following cell detachment (SupplementaryFigure S4D). Because metastatic cancer cells need to survive the rigors of the dissemination journey, resistance to anoikis is a prerequisite for metastasis [57]. 4T1 cancer cells are highly metastatic [58]. "
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    ABSTRACT: The Warburg effect, which reflects cancer cells' preference for aerobic glycolysis over glucose oxidation, contributes to tumor growth, progression and therapy resistance. The restraint on pyruvate flux into mitochondrial oxidative metabolism in cancer cells is in part attributed to the inhibition of pyruvate dehydrogenase (PDH) complex. Src is a prominent oncogenic non-receptor tyrosine kinase that promotes cancer cell proliferation, invasion, metastasis and resistance to conventional and targeted therapies. However, the potential role of Src in tumor metabolism remained unclear. Here we report that activation of Src attenuated PDH activity and generation of reactive oxygen species (ROS). Conversely, Src inhibitors activated PDH and increased cellular ROS levels. Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1). Indeed, Src was the main kinase responsible for PDHA1 tyrosine phosphorylation in cancer cells. Expression of a tyrosine-289 non-phosphorable PDHA1 mutant in Src-hyperactivated cancer cells restored PDH activity, increased mitochondrial respiration and oxidative stress, decreased experimental metastasis, and sensitized cancer cells to pro-oxidant treatment. The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.
    Full-text · Article · Feb 2016 · Oncotarget
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    • "Several recent reports show that ectopic TrkB overexpression in rat and human kidney epithelial cells acts as a potent anoikis suppressor through AKT activation (Douma et al., 2004; Geiger and Peeper, 2005). Additionally, this ectopic overexpression promotes epithelial-to-mesenchymal transition (EMT) through induction of Zeb1, an E-cadherin repressor (Smit and Peeper, 2011). "
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    ABSTRACT: In metastatic breast cancer, the acquisition of malignant traits has been associated with the increased rate of cell growth and division, mobility, resistance to chemotherapy, and invasiveness. While screening for the key regulators of cancer metastasis, we observed that neurotrophin receptor TrkB is frequently overexpressed in breast cancer patients and breast cancer cell lines. Additionally, we demonstrate that TrkB expression and clinical breast tumor pathological phenotypes show significant correlation. Moreover, TrkB expression was significantly upregulated in basal-like, claudin-low, and metaplastic breast cancers from a published microarray database and in patients with triple-negative breast cancer, which is associated with a higher risk of invasive recurrence. Interestingly, we identified a new TrkB-regulated functional network that is important for the tumorigenicity and metastasis of breast cancer. We demonstrated that TrkB plays a key role in regulation of the tumor suppressors Runx3 and Keap1. A markedly increased expression of Runx3 and Keap1 was observed upon knockdown of TrkB, treatment with a TrkB inhibitor, and in TrkB kinase dead mutants. Additionally, the inhibition of PI3K/AKT activation significantly induced Runx3 and Keap1 expression. Furthermore, we showed that TrkB enhances metastatic potential and induces proliferation. These observations suggest that TrkB plays a key role in tumorigenicity and metastasis of breast cancer cells through suppression of Runx3 or Keap1 and that it is a promising target for future intervention strategies for preventing tumor metastasis and cancer chemoprevention.
    Preview · Article · Dec 2015 · Moleculer Cells
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    • "TrkB, which initiates the survival signal during neural development, may play a conflicting role such as regulating tumor suppressive functions, which are driven by apoptosis. As TrkB is also reported to be involved in regulating tumor invasion and metastasis in some adult cancers 26–28, these candidate compounds might also be used as drugs against the other advanced cancers with expression of TrkB. "
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    ABSTRACT: Neuroblastoma (NB) is one of the most frequent solid tumors in children and its prognosis is still poor. The neurotrophin receptor TrkB and its ligand brain-derived neurotrophic factor (BDNF) are expressed at high levels in high-risk NBs and are involved in defining the poor prognosis of the patients. However, the TrkB targeting therapy has never been realized in the clinic. We performed an in silico screening procedure utilizing an AutoDock/grid computing technology in order to identify novel small chemical compounds targeting the BDNF-binding domain of TrkB. For the first screening, a library of three million synthetic compounds was screened in silico and was ranked according to the Docking energy. The top-ranked 37 compounds were further functionally screened for cytotoxicity by using NB cell lines. We have finally identified seven compounds that kill NB cells with the IC50 values of 0.07–4.6 μmol/L. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that these molecules induce apoptosis accompanied by p53 activation in NB cell lines. The candidate compounds and BDNF demonstrated an antagonistic effect on cell growth, invasion, and colony formation, possibly suggesting competition at the BDNF-binding site of TrkB. The candidate compounds had tumor-suppressive activity in xenograft and in vivo toxicity tests (oral and intravenous administrations) using mice, and did not show any abnormal signs. Using in silico Docking screening we have found new candidate TrkB inhibitors against high-risk NBs, which could lead to new anti-cancer drugs.
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