Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo

Berger, Michael; Neth, Olaf; Ilmer, Matthias; Garnier, Agnès; Salinas-Martín, Manuel Vicente; Asencio, Juan Carlos de Agustín; Schweinitz, Dietrich von; Kappler, Roland; Muñoz, Miguel

doi:10.1016/j.jhep.2013.12.024

Cited by 106 publications

(161 citation statements)

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“…2-4). First, the truncated variant was investigated, due to its significance in HB as a potential therapeutic target (8). In order to accomplish this, the relative expression of tr-TACR1 was correlated with a recently described 16-gene molecular signature known to be associated with prognosis (16).…”

Section: Tacr1 Expression Does Not Correlate With Biological Charactementioning

confidence: 99%

“…Aprepitant, a non-peptide NK1R antagonist, is a clinical agent approved by the Food and Drug Administration for the treatment of chemotherapy-induced nausea and vomiting. Its effects as an anticancer agent have been described extensively in vitro and in vivo (6)(7)(8)(9)(10)(11). Notably, evidence indicates that it has limited toxic side effects even when administered in high doses (6,12).…”

Section: Introductionmentioning

confidence: 99%

“…In a previous study, we described that TACR1 is highly expressed in human HB, predominantly in its truncated form [truncated-TACR1 (tr-TACR1)] (8). Compared with full-length (fl-TACR1), tr-NK1R lacks 96 amino acids at the cytoplasmic C-terminus of the receptor that are responsible for intracellular signal transduction.…”

Section: Introductionmentioning

confidence: 99%

“…Compared with full-length (fl-TACR1), tr-NK1R lacks 96 amino acids at the cytoplasmic C-terminus of the receptor that are responsible for intracellular signal transduction. Although this splice variant is considered to be able to couple G proteins, it exhibits decreased efficiency with respect to internalization and desensitization (8,(13)(14)(15). The net result of this is a decreased ability for negative feedback inhibition, allowing constant activation despite saturation of the receptor complex (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

“…This, in turn, may contribute to the correlation of expression of this particular splice variant with cancer. In an experimental HB setting, NK1R antagonists acted as highly active anticancer agents in vitro and in vivo, and functioned synergistically with established chemotherapy agents in vitro (8).…”

Section: Introductionmentioning

confidence: 99%

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Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

et al. 2015

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Abstract. The substance P (SP; also known as TAC1)/neurokinin-1 receptor (NK1R; also known as TACR1) complex is a critical part in the development of cancer. Therefore, NK1R antagonists, such as the clinical drug aprepitant, are currently under investigation as future anticancer agents. In a previous study, NK1R (TACR1) was identified as a potent anticancer target in hepatoblastoma (HB). However, little is known regarding the exact distribution of this target among HB subsets and whether it correlates with clinical features and prognosis. In the present study, mRNA was isolated from 47 children with HB, and reverse transcription-quantitative polymerase chain reaction was performed on the samples to analyze the expression of full-length-TACR1 (fl-TACR1) and truncated-TACR1 (tr-TACR1). These data were correlated with data obtained from 9 tumor-free controls, as well as with the presence of metastasis, PRETEXT, vascular invasion, histology, age of diagnosis, multifocality, CTNNB1 mutation, gender and overall survival. Additionally, the present study investigated a recently described 16-gene signature characteri zing HB known to correlate with prognosis. Compared with tumor-free liver tissue, tumorous tissue expressed TACR1 significantly higher for the truncated version (P=0.0301), and by trend also for the full-length version. Accordingly, the expression of fl-TACR1 correlated with the expression of the truncated version (P=0.0074). Furthermore, a low expression of fl-TACR1 correlated with characteristics of the 16-gene signature known to predict prognosis (P=0.0222). However, there was no correlation between tr-TACR1 and the tumor characteristics investigated, including outcome, although a clear trend was observed for some tumor characteristics. The current results reinforced the previously described findings that in HB, tr-TACR1 is overexpressed compared with tumor-free liver tissue. Furthermore, to the best of our knowledge, the present study demonstrated for the first time that tr-TACR1 is expressed ubiquitously among the different subsets of HB. Therefore, NK1R may serve as a potent anticancer target in a large variety of patients with HB, independent of tumor biology and clinical stage.

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Section: Tacr1 Expression Does Not Correlate With Biological Charactementioning

confidence: 99%