Interplay between autophagy and apoptosis in TrkA-induced cell death

Dadakhujaev, Shorafidinkhuja; Jung, Eun Joo; Noh, Hae Sook; Hah, Young‐Sool; Kim, Chang Jae; Kim, Deok Ryong

doi:10.4161/auto.5.1.7276

Cited by 29 publications

(22 citation statements)

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“…For example, NGF treatment of TrkA-expressing medulloblastoma cells induces cell death (45), and pheochromocytoma PC12 cells expressing TrkA were rendered susceptible to cell death following NGF-treatment (46). Similarly, the expression of TrkA in rat glioma cell line reduced its invasiveness in correlation with a higher rate of apoptosis (47), whereas TrkA-transfected U2OS osteosarcoma cells also underwent cell death (48). These results with TrkA and NGF raise the question of whether TrkC functions as a tumor suppressor only via its dependence receptor activity, or whether NT-3 contributes to this activity.…”

Section: Discussionmentioning

confidence: 99%

Dependence receptor TrkC is a putative colon cancer tumor suppressor

Genevois

Ichim

Coissieux

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The TrkC neurotrophin receptor belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase receptor and therefore generally considered to be a protooncogene. We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Furthermore, reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation, as well as in vivo tumor growth. Finally, we provide evidence that a mutation of TrkC detected in a sporadic cancer is a loss-ofproapoptotic function mutation. Together, these data support the conclusion that TrkC is a colorectal cancer tumor suppressor.neurotrophin-3 | caspase-3 | genetic | epigenetic T he Trk tyrosine kinase receptors and their ligands, the neurotrophins, have been studied extensively for their role in nervous system development. However, TrkA was originally cloned as an oncogene from colon carcinoma tumors in which the TrkA kinase domain was fused to the tropomyosin gene in the extracellular domain (1). This discovery motivated a great number of studies, which showed that neurotrophins (NGF, BDNF, and NT-4/5, NT-3) and their respective Trk receptors (TrkA, TrkB, and TrkC), are all involved in various malignancies (for review, see ref.2). The initial (and still generally accepted) view is that Trks, like other tyrosine kinase receptors, are oncogenic receptors, and therefore pan-Trk kinase inhibitors are currently being tested in clinical trials (3-5). Somewhat surprisingly, however, it has turned out that, at least in tumors such as neuroblastoma and medulloblastoma, TrkA, TrkB, and TrkC behave very differently, despite their close homology. TrkA and TrkC expression is associated with a good prognosis, whereas TrkB is expressed in very aggressive tumors (for review; see ref.2). The fact that the high expression of a tyrosine kinase receptor known to activate prooncogenic pathways (like the MAPK and PI3K-AKT pathways) is associated with a better outcome is counter intuitive, and suggests the possibility that TrkA and TrkC, rather than functioning solely as oncogenes, may also, in at least some cases, act as tumor suppressors. Although this notion may be ostensibly paradoxical, two recent independent studies have lent support to it, by demonstrating that both TrkA and TrkC, but not TrkB, act as dependence receptors (6, 7).Dependence receptors, which also include DCC (Deleted in Colorectal Carcinoma), UNC5H, Patched, Ne...

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Section: Discussionmentioning

confidence: 99%

Dependence receptor TrkC is a putative colon cancer tumor suppressor

Genevois

Ichim

Coissieux

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, the effect of NGF on cells coexpressing TRKA and p75NTR has often been linked to cell differentiation or growth inhibition. However, very recent studies have shown that, in addition to p75NTR and under certain circumstances, TRKA may trigger an apoptotic signaling (37)(38)(39)(40). Therefore, it may be possible that, in our conditions and particularly when TRKA and p75NTR expression is forced, NGF can convey an intracellular cell death message through both receptors.…”

Section: Discussionmentioning

confidence: 99%

A SP1/MIZ1/MYCN Repression Complex Recruits HDAC1 at theTRKAandp75NTRPromoters and Affects Neuroblastoma Malignancy by Inhibiting the Cell Response to NGF

et al. 2011

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Neuroblastoma is the most common extracranial solid tumor of childhood. One important factor that predicts a favorable prognosis is the robust expression of the TRKA and p75NTR neurotrophin receptor genes. Interestingly, TRKA and p75NTR expression is often attenuated in aggressive MYCN-amplified tumors, suggesting a causal link between elevated MYCN activity and the transcriptional repression of TRKA and p75NTR, but the precise mechanisms involved are unclear. Here, we show that MYCN acts directly to repress TRKA and p75NTR gene transcription. Specifically, we found that MYCN levels were critical for repression and that MYCN targeted proximal/core promoter regions by forming a repression complex with transcription factors SP1 and MIZ1. When bound to the TRKA and p75NTR promoters, MYCN recruited the histone deacetylase HDAC1 to induce a repressed chromatin state. Forced re-expression of endogenous TRKA and p75NTR with exposure to the HDAC inhibitor TSA sensitized neuroblastoma cells to NGF-mediated apoptosis. By directly connecting MYCN to the repression of TRKA and p75NTR, our findings establish a key pathway of clinical pathogenicity and aggressiveness in neuroblastoma. Cancer Res; 71(2); 404-12. Ó2010 AACR.

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“…Caspase activation and apoptosis markers were not seen, rather the authors identified autophagic vacuoles by electron microscopy, and showed occurrence of a number of hallmarks of autophagy (Hansen et al, 2007). A mix of apoptotic and autophagic cell death mechanisms was reported in TrkAtransfected U2OS osteosarcoma cells (Dadakhujaev et al, 2009). TrkA overexpression in U2OS cells leads to caspase-7 activation and production of truncated BAX, in parallel with autophagosome formation and LC3 lipidation.…”

Section: Trk-induced Death In Other Cell Typesmentioning

confidence: 99%

“…TrkA overexpression in U2OS cells leads to caspase-7 activation and production of truncated BAX, in parallel with autophagosome formation and LC3 lipidation. Furthermore, depletion of autophagic effectors such as Atg5 or Beclin1 inhibited TrkA-induced cell death in U2OS cells (Dadakhujaev et al, 2009).…”

Section: Trk-induced Death In Other Cell Typesmentioning

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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Interplay between autophagy and apoptosis in TrkA-induced cell death

Cited by 29 publications

References 20 publications

Dependence receptor TrkC is a putative colon cancer tumor suppressor

Dependence receptor TrkC is a putative colon cancer tumor suppressor

A SP1/MIZ1/MYCN Repression Complex Recruits HDAC1 at theTRKAandp75NTRPromoters and Affects Neuroblastoma Malignancy by Inhibiting the Cell Response to NGF

On the death Trk

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