Autoregulation of endothelin-1 secretion by cultured human keratinocytes via the endothelin B receptor

Yohn, Joseph; Smith, Christopher M.; Stevens, Troy; Morelli, Joseph G.; Shurnas, Libby R.; Walchak, Sandra J.; Hoffman, T. A.; Kelley, Kim K.; Escobedo-Morse, Antonio; Yanagisawa, Masashi; Kane, Madeleine A.; Zamora, Martin R.

doi:10.1016/0167-4889(94)90282-8

Cited by 22 publications

(10 citation statements)

References 23 publications

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“…Support for the second analgesic mechanism comes from our finding that ET-1 levels in the cell supernatant were significantly lower in oral SCC re-expressing the ET B receptor. ET B receptors have a known role in ET-1 clearance and inhibiting ET-1 secretion in keratinocytes [26; 38]. Our previous studies in a mouse oral SCC model have shown that ET-1 protein and mRNA concentrations are markedly elevated in oral SCC tumors.…”

Section: Discussionmentioning

confidence: 99%

Re-expression of the methylated EDNRB gene in oral squamous cell carcinoma attenuates cancer-induced pain

Viet

Dang

et al. 2011

Pain

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Endothelin-1 is a vasoactive peptide that activates both the endothelin A (ETA) and endothelin B (ETB) receptors, and is secreted in high concentrations in many different cancer environments. While ETA receptor activation has an established nociceptive effect in cancer models, the role of ETB receptors on cancer pain is controversial. EDNRB, the gene encoding the ETB receptor, has been shown to be hypermethylated and transcriptionally silenced in many different cancers. In this study we demonstrate that EDNRB is heavily methylated in human oral SCC lesions, which are painful, but not methylated in human oral dysplasia lesions, which are typically not painful. ETB mRNA expression is reduced in the human oral SCC lesions as a consequence of EDNRB hypermethylation. Using a mouse cancer pain model we show that ETB receptor re-expression attenuates cancer-induced pain. These findings identify EDNRB methylation as a novel regulatory mechanism in cancer-induced pain and suggest that demethylation therapy targeted at the cancer microenvironment has the potential to thwart pain-producing mechanisms at the source, thus freeing patients of systemic analgesic toxicity.

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Section: Discussionmentioning

confidence: 99%

Re-expression of the methylated EDNRB gene in oral squamous cell carcinoma attenuates cancer-induced pain

Viet

Dang

et al. 2011

Pain

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“…[3] Unlike the G proteins associated with ETAR, ETBR predominantly interacts with G αi 1, G αi 2, and G αq /11. [61] ETBR is expressed by various normal cell types [47], including dorsal root ganglion satellite cells, nonmyelinating ensheathing Schwann cells [51], skin keratinocytes [67,33], and human gingival keratinocytes. [23] ETBR is also found on different cancer cells, such as melanoma [34], breast carcinoma [2,65], and oral squamous carcinoma cell line SCC25.…”

Section: Discussionmentioning

confidence: 99%

Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice

Quang¹,

Schmidt²

2010

Pain

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Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10 −4 M, 10 −5 M, and 10 −6 M BQ-3020) significantly increased production of β-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3 mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3 hours post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300 μg/kg and 3 mg/kg) had no effects. Local naloxone methiodide (500 μg/kg) or selective μ-opioid receptor antagonist (CTOP, 500 μg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating β-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment.

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“…265, 266 The latter comprises an autocrine loop, but with a biphasic dynamic response; immediately upon exposure to ET-1 keratinocytes show elevated intracellular Ca 2+ , which would be expected to cause an acute increase in the release of many substances, including ET-1 itself, but after prolonged (24 h) exposure to ET-1, its basal release by keratinocytes is suppressed, probably by negative feedback on its synthesis. 266 Without this dampening, counteracting mechanism, the initial release of a small amount of ET-1 would further activate ET B receptors on keratinocytes and continuously stimulate its own release. The β-endorphin released by keratinocytes exerts an analgesic and anti-hyperalgesic action, binding to μ-opiate receptors on the nociceptor nerve endings and opening G protein-sensitive K + channels, thereby lowering excitability and the generation of action potentials 129…”

Section: Cell Physiological Responses To Endothelinsmentioning

confidence: 99%

Endothelin Receptors and Pain

Khodorova

Montmayeur

Strichartz

2009

The Journal of Pain

147

110

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In this paper we review the biochemistry, second messenger pathways and hetero-receptor coupling that are activated by ET receptors, the cellular physiological responses to ET receptor activation, and the contribution to pain of such mechanisms occurring in the periphery and the CNS. Our goal is to frame the subject of endothelin and pain for a broad readership, and to present the generally accepted as well as the disputed concepts, including important unanswered questions.

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Autoregulation of endothelin-1 secretion by cultured human keratinocytes via the endothelin B receptor

Cited by 22 publications

References 23 publications

Re-expression of the methylated EDNRB gene in oral squamous cell carcinoma attenuates cancer-induced pain

Re-expression of the methylated EDNRB gene in oral squamous cell carcinoma attenuates cancer-induced pain

Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice

Endothelin Receptors and Pain

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