ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

Allouche, Michèle

doi:10.4161/cc.6.13.4433

Cited by 34 publications

(27 citation statements)

References 61 publications

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“…To note, no correlation between PTN (a Mdk-related protein with high homology with Mdk) expression and resistance to THC-induced cell death was found in this study (Supplementary Figure 4B), which further supports that the mechanism of resistance to THC-induced cell death in glioma cells specifically relies on the increased expression of Mdk. Our data are therefore in agreement -at least in part -with the proposal that ALK is a dependence receptor 27,33 that has an antiapoptotic role only when is activated/stimulated by its ligand. Of potential therapeutic relevance, we found that increased expression of Mdk is associated with decreased survival of GBM patients, which further supports that this ligand may have an important role in promoting resistance to cancer therapies.…”

Section: Discussionsupporting

confidence: 91%

Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action

et al. 2011

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Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. D 9 -Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagymediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas.

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Section: Discussionsupporting

confidence: 91%

Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action

et al. 2011

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“…It was initially identified as part of the oncogenic nucleophosmin-ALK fusion protein resulting from the t(2;5) translocation that is frequently associated with anaplastic large-cell lymphoma (Morris et al, 1994). Nucleophosmin allows dimerization of the fusion protein, causing constitutive activation of ALK kinase and downstream activation of phospholipase C-g, PI3K, STATs and pp60c-src (Allouche, 2007). The native full-length ALK receptor is mainly expressed in discrete regions of the developing central and peripheral nervous system (Iwahara et al, 1997).…”

Section: Dependence Receptors: a Short Historymentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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Dependence receptors (DRs) now form a family of more than a dozen membrane receptors that are not linked by their structure, but by common functional traits. The most notable is their ability to trigger two opposite signaling pathways: in the presence of ligand, these receptors activate classic signaling pathways implicated in cell survival, migration and differentiation. In the absence of ligand, they do not stay inactive, rather they elicit an apoptotic signal. Thus, cells expressing this kind of receptor are dependent on the presence of ligand in the extracellular environment to survive. This review will recapitulate the increasing data regarding the molecular mechanisms associated with DRs, their potential implication during development, as well as their deregulation during tumorigenesis and, finally, their emergence as new possible therapeutic targets for cancer treatment.

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“…7 Consequent to these rearrangements, ALK is constitutively expressed as a phosphorylated fusion product displaying tumorigenic activity. 8,9 ALK fusion proteins serve as specific immunohistochemical markers 2,3 and are potential therapeutic targets for ALKkinase inhibitors. 10 Soda et al 11 recently identified a transforming EML4-ALK fusion gene in 6.7% of smoker non-small-lung cancer (NSCLC) patients from Japan.…”

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confidence: 99%

EML4-ALK Rearrangement in Non-Small Cell Lung Cancer and Non-Tumor Lung Tissues

Martelli

Sozzi

Hernández

et al. 2009

The American Journal of Pathology

281

207

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A fusion gene, echinoderm microtubule associated protein like 4 -anaplastic lymphoma kinase (EML4-ALK), with transforming activity has recently been identified in a subset of non-small cell lung cancer (NSCLC), but its pathogenetic, diagnostic, and therapeutic roles remain unclear. Both frequency and type of EML4-ALK transcripts were investigated by reverse transcription PCR in 120 frozen NSCLC specimens from Italy and Spain; non-neoplastic lung tissues taken far from the tumor were used as controls. In cases carrying the fusion transcript, we determined EML4-ALK gene and protein levels using fluorescence in situ hybridization, Western blotting, and immunoprecipitation. We also analyzed ALK protein levels in paraffin samples from 662 NSCLC specimens, including the 120 cases investigated in the molecular studies. EML4-ALK transcripts (variants 1 and 3) were detected in 9 of 120 NSCLC samples but were not specific for NSCLC since they were also found in noncancerous lung tissues taken far from the tumor. Notably, no transcripts were detected in matching tumor samples from these patients. Fluorescence in situ hybridization analysis of cases expressing EML4-ALK transcripts showed that only a minority of cells harbored the EML4-ALK gene. None of these cases was found to express the EML4-ALK protein as examined by immunohistochemistry, Western blotting, and immunoprecipitation. The EML4-ALK transcript cannot be regarded as a specific diagnostic tool for NSCLC. Our results show therefore that the causal role and value of EML4-ALK as a therapeutic target remain to be defined.

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ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

Cited by 34 publications

References 61 publications

Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action

Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action

Dependence receptors: a new paradigm in cell signaling and cancer therapy

EML4-ALK Rearrangement in Non-Small Cell Lung Cancer and Non-Tumor Lung Tissues

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