A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

Chou, Thomas T.; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1074/jbc.275.1.565

Cited by 57 publications

(48 citation statements)

References 44 publications

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“…This result is consistent with the reports of Chou et al (61,62) that TrkA-induced medulloblastoma apoptosis is independent of Erk1/2, JNK, and p38 MAPK. Therefore it is possible that TrkA induces a Ras and/or Raf-dependent, but MEK/Erk1/2-independent pathway that would be responsible for TrkA-induced apoptosis, as it has been suggested for MB (61).…”

Section: Discussionsupporting

confidence: 83%

“…The only difference we observed in the signaling proteins stimulated by these receptors was a much greater enhancement of sustained Erk1/2 phosphorylation by TrkA. However, suppression of MEK/MAPK activity did not inhibit TrkA-mediated cell death, and TrkA did not increase p38 MAPK activity, which occurs in PC12 cells overexpressing TrkA (31,61). This result is consistent with the reports of Chou et al (61,62) that TrkA-induced medulloblastoma apoptosis is independent of Erk1/2, JNK, and p38 MAPK.…”

Section: Discussionmentioning

confidence: 66%

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TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

Lavoie

LeSauteur

Kohn

et al. 2005

Journal of Biological Chemistry

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Neuroblastoma (NB) is the most frequent solid extracranial tumor in children. Its clinical prognosis correlates with the expression of members of the Trk neurotrophin receptor family, which includes TrkA and TrkB. TrkA expression is associated with favorable prognosis, whereas TrkB expression is associated with poor prognosis. Here we show that TrkA expression induces the apoptosis of NB cells and does so by modulating the levels or activities of a number of proteins involved in regulating cell survival and apoptosis, including p53, Bcl-2, and caspase-3. TrkA increased the expression of p53 target proteins and failed to induce apoptosis in cells where p53 was inactivated by mutation or via expression of dominant inhibitory p53 or E1B55K, indicating that TrkA mediates apoptosis, at least in part, through p53. Treatment with a caspase inhibitor or overexpression of Bcl-X L also prevented TrkA from inducing apoptosis. In contrast, elevated expression of TrkA in non-transformed sympathetic neurons resulted in the suppression of p53 levels and enhanced survival. These results identify apoptosis as a novel biological response of TrkA in NB cells and imply that TrkA is a good prognosis marker for NB due in part to its ability to mediate apoptosis when expressed at sufficient levels. Neuroblastoma (NB)1 is the most common solid extracranial solid tumor of childhood and likely arises from sympathoadrenal precursor cells. The median age at diagnosis is ϳ18 months, and spontaneous tumor regression is frequently observed in patients diagnosed at 1 year of age or younger. In contrast, children older than 1 year diagnosed with NB often experience aggressive tumors that are disseminated, resistant to chemotherapy, and metastasized to bone, and often fatal. An important correlative characteristic of NB is the expression of two of the neurotrophin receptors, the TrkA/nerve growth factor (NGF) receptor and the TrkB/brain-derived neurotrophic factor receptor (1-4). The expression of TrkB, a poor prognosis marker, mediates survival, proliferation, and chemotherapeutic drug resistance (5-10), whereas expression of TrkA, a favorable prognosis marker, induces cell growth arrest and differentiation of cultured NB cells (11)(12)(13). This is consistent with TrkA being expressed in tumors that spontaneously regress. Most NB cell lines, which are derived from malignant tumors, lack or have very low levels of TrkA protein expression. Cell lines with low TrkA expression respond to NGF by differentiating into neuronal-like cells (11). Similarly, expression of TrkA by transfection converts NGF non-responsive NB cells into NGF-responsive cells, both in culture and in vivo, with the typical responses being the cessation of cell growth and differentiation into neural and Schwann cells (12). Thus, TrkA converts malignant NB cells into quiescent differentiated cells.An alternative or additional explanation for why TrkA is a good prognosis marker for NB that might contribute to spontaneous tumor regression is that it may induce apoptosis. Paradoxic...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 66%

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

Lavoie

LeSauteur

Kohn

et al. 2005

Journal of Biological Chemistry

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“…NGF application to wild type medulloblastoma cells or to p75 or TrkC expressing cells had no effect on viability. The death effect was inhibited by K-252A, an inhibitor of TrkA phosphorylation; and likewise was abolished in kinase-dead or signaling tyrosine mutants of TrkA, as well as by a dominant-negative Ras inhibitor (Chou et al, 2000). Pomeroy, Segal, and coworkers carried out a detailed study on TrkC effects in medulloblastoma, and showed that NT-3 stimulation induced death of primary tumor cells in culture under serumfree conditions (Kim et al, 1999).…”

Section: Trk-induced Death In Medulloblastoma and Neuroblastoma Cellsmentioning

confidence: 99%

On the death Trk

Harel

Costa

Fainzilber

2010

Developmental Neurobiology

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ABSTRACT:The trk family of receptor tyrosine kinases supports survival and differentiation in the nervous system. Paradoxically it has also been shown that members of the trk family can induce cell death in pediatric tumor cells of neuronal origin. Moreover, TrkA and TrkC serve as good prognostic indicators in neuroblastoma and medulloblatoma, respectively. Although the possible linkage between these observations was intriguing, until recently there was limited insight on the mechanisms involved. Recent findings suggest that TrkA might influence neuronal cell death through stimulation of p75 cleavage. An alternative p75-independent mechanism was suggested by a newly discovered interaction between TrkA and CCM2 (the protein product of the gene cerebral cavernous malformation 2). Coexpression of CCM2 with TrkA induces cell death in medulloblastoma and neuroblastoma cells, and CCM2 expression levels correlate with those of TrkA and with good prognosis in neuroblastoma patients. Thus, mechanistic clues to the enigma of trk-induced cell death have begun to emerge. Detailed elucidation of these mechanisms and their in vivo physiological significance will be of keen interest for future research. '

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“…The effects of NGF/tropomyosin receptor kinase A (TrkA) in cancer appear to be related to the cell type. For instance, NGF/TrkA induces differentiation, apoptosis, and growth inhibition in neuroblastoma and medulloblastoma (Chou et al ., 2000; Lavenius et al ., 1995; Matsushima and Bogenmann, 1993), and high expression of TrkA is considered a favorable prognostic indicator in neuroblastoma (Nakagawara et al ., 1993). Whereas TrkAI splice variant was found to induce these effects, the TrkAIII splice variant was shown to possess significant oncogenic effects in neuroblastoma (Farina et al ., 2015; Tacconelli et al ., 2004).…”

Section: Introductionmentioning

confidence: 99%

TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK⁺ T‐cell lymphoma

Shi

George

et al. 2017

Molecular Oncology

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Nucleophosmin‐anaplastic lymphoma kinase‐expressing (NPM‐ALK +) T‐cell lymphoma is an aggressive neoplasm that is more commonly seen in children and young adults. The pathogenesis of NPM‐ALK + T‐cell lymphoma is not completely understood. Wild‐type ALK is a receptor tyrosine kinase that is physiologically expressed in neural tissues during early stages of human development, which suggests that ALK may interact with neurotrophic factors. The aberrant expression of NPM‐ALK results from a translocation between the ALK gene on chromosome 2p23 and the NPM gene on chromosome 5q35. The nerve growth factor (NGF) is the first neurotrophic factor attributed to non‐neural functions including cancer cell survival, proliferation, and metastasis. These functions are primarily mediated through the tropomyosin receptor kinase A (TrkA). The expression and role of NGF/TrkA in NPM‐ALK + T‐cell lymphoma are not known. In this study, we tested the hypothesis that TrkA signaling is upregulated and sustains the survival of this lymphoma. Our data illustrate that TrkA and NGF are expressed in five NPM‐ALK + T‐cell lymphoma cell lines and TrkA is expressed in 11 of 13 primary lymphoma tumors from patients. In addition, we found evidence to support that NPM‐ALK and TrkA functionally interact. A selective TrkA inhibitor induced apoptosis and decreased cell viability, proliferation, and colony formation of NPM‐ALK + T‐cell lymphoma cell lines. These effects were associated with downregulation of cell survival regulatory proteins. Similar results were also observed using specific knockdown of TrkA in NPM‐ALK + T‐cell lymphoma cells by siRNA. Importantly, the inhibition of TrkA signaling was associated with antitumor effects in vivo, because tumor xenografts in mice regressed and the mice exhibited improved survival. In conclusion, TrkA plays an important role in the pathogenesis of NPM‐ALK + T‐cell lymphoma, and therefore, targeting TrkA signaling may represent a novel approach to eradicate this aggressive neoplasm.

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A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

Cited by 57 publications

References 44 publications

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

On the death Trk

TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK⁺ T‐cell lymphoma

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A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

Cited by 57 publications

References 44 publications

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

On the death Trk

TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK+ T‐cell lymphoma

Contact Info

Product

Resources

About

TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK⁺ T‐cell lymphoma