QGP-1 cells release 5-HT via TRPA1 activation; a model of human enterochromaffin cells

Doihara, Hitoshi; Nozawa, Katsura; Kojima, Ryosuke; Kawabata-Shoda, Eri; Yokoyama, Toshihide; Ito, Hiroyuki

doi:10.1007/s11010-009-0165-7

Cited by 62 publications

(61 citation statements)

References 34 publications

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“…We used the human pancreatic neuroendocrine tumor cells BON-1, which express sstr 2 at low to medium levels (11); the human prostate cancer cells PC3, which also express sstr 2 at low to medium levels (11); the human pancreatic islet cell carcinoma cells QGP1 (12), which express sstr 2 at low levels; and the rat pancreatic acinar cells AR42J, which express sstr 2 at high levels (13). We cultured all cells at 37°C and 5% CO 2 in Dulbecco modified Eagle medium or RPMI containing GlutaMAX (Thermo Fischer Scientific), 10% (v/v) fetal bovine serum, penicillin (100 U/mL), and streptomycin (100 mg/mL).…”

Section: Cell Modelsmentioning

confidence: 99%

Upregulation of Key Molecules for Targeted Imaging and Therapy

et al. 2016

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Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches. Methods: We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr 2 ). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo. Results: We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr 2 on transcriptional, translational, and functional levels in a time-and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr 2 upregulation improved the tumor-to-background and tumor-tokidney ratios, which are the key determinants of successful sstr 2 -targeted imaging and radiopeptide therapy. Conclusion: We present an approach that uses epigenetic modifiers to improve sstr 2 targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates.

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Section: Cell Modelsmentioning

confidence: 99%

Upregulation of Key Molecules for Targeted Imaging and Therapy

et al. 2016

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“…Among the most frequently used PanNET cell lines are QGP-1 and BON-1. QGP-1 was established in 1980 from a somatostatin-producing islet cell carcinoma (Kaku et al 1980, Iguchi et al 1990 and it has been used to study the molecular mechanisms that regulate tumour cell proliferation (Doihara et al 2009, Valentino et al 2014. BON-1 was established in 1991 from a lymph node metastasis of a PanNET patient (Evers et al 1991) and has been used as a model for studying the molecular mechanisms of PanNETs and their sensitivity to therapy.…”

Section: Introductionmentioning

confidence: 99%

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

Hofving¹,

Arvidsson²,

Almobarak³

et al. 2018

Endocrine-Related Cancer

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Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.

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“…In addition to its expression in sensory neurons, TRPA1 is widely expressed in the digestive system not only in peripheral nerve fibers but also in 5-HT-releasing ECs and cholecystokinin-releasing endocrine cells of the gastrointestinal mucosa (Purhonen et al, 2008;Nozawa et al, 2009). We therefore tested whether apomorphine can activate TRPA1 in the QGP-1 cell line, a human pancreatic endocrine cell line that was found to highly express TRPA1 and EC cell marker genes (Doihara et al, 2009c). As expected, apomorphine caused strong rises in intracellular calcium that could be completely prevented when QGP-1 cells were preincubated with HC-030031 (Fig.…”

Section: Resultsmentioning

confidence: 79%

“…We next examined whether QGP-1 cells can release 5-HT in response to apomorphine, which has already been described for AITC and cinnamaldehyde (Doihara et al, 2009b). For maximal response, we chose a high agonist concentration of 300 mM, which was previously shown to be effective for AITC-induced release of 5-HT in QGP-1 cells (Doihara et al, 2009c). Stimulation of QGP-1 cells with apomorphine provoked a rise in the 5-HT concentration in the supernatant of QGP-1 cells comparable with AITC.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to its predominant expression in sensory neurons of the dorsal root and trigeminal ganglia, where TRPA1 contributes to the sensation of chemical pain, recent evidence also suggests its presence in a variety of non-neuronal cells, including skin cells (Atoyan et al, 2009;Oehler et al, 2012) and cells within the respiratory tract (Nassini et al, 2012) and the gastrointestinal tract (Stokes et al, 2006). In enterochromaffin cells (ECs), for example, a possible contribution of TRPA1 to the regulation of gastrointestinal motility might base on a release of serotonin upon channel activation (Doihara et al, 2009c;Nozawa et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Apomorphine Is a Bimodal Modulator of TRPA1 Channels

et al. 2012

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Apomorphine is a non-narcotic derivative of morphine, which acts as a dopamine agonist and is clinically used to treat "offstates" in patients suffering from Parkinson's disease. Adverse effects of apomorphine treatment include severe emesis and nausea, and ulceration and pain at the injection site. We wanted to test whether sensory transient receptor potential (TRP) channels are a molecular target for apomorphine. Here, we show that rTRPV1, rTRPV2, rTRPV3, and mTRPV4, as well as hTRPM8, and rTRPM3, which are expressed in dorsal root ganglion neurons, are insensitive toward apomorphine treatment. This also applied to the cellular redox sensor hTRPM2. On the contrary, human TRPA1 could be concentrationdependently modulated by apomorphine. Whereas the addition of apomorphine in the low micromolar range produced an irreversible activation of the channel, application of higher concentrations caused a reversible voltage-dependent inhibition of heterologously expressed TRPA1 channels, resulting from a reduction of single-channel open times. In addition, we provide evidence that apomorphine also acts on endogenous TRPA1 in cultured dorsal root ganglion neurons from rats and in the enterochromaffin model cell line QGP-1, from which serotonin is released upon activation of TRPA1. Our study shows that human TRPA1 is a target for apomorphine, suggesting that an activation of TRPA1 might contribute to adverse side effects such as nausea and painful injections, which can occur during treatment with apomorphine.

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QGP-1 cells release 5-HT via TRPA1 activation; a model of human enterochromaffin cells

Cited by 62 publications

References 34 publications

Upregulation of Key Molecules for Targeted Imaging and Therapy

Upregulation of Key Molecules for Targeted Imaging and Therapy

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

Apomorphine Is a Bimodal Modulator of TRPA1 Channels

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