Rat somatostatin sst<sub>2(a)</sub> and sst<sub>2(b)</sub> receptor isoforms mediate opposite effects on cell proliferation

Alderton, Forbes; Fan, Tai-Ping; Schindler, Marcus; Humphrey, P. P. A.

doi:10.1038/sj.bjp.0702282

Cited by 19 publications

(13 citation statements)

References 15 publications

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“…However, its immunopositivity was found in human breast cancers [8]. If the preferential expression of sst2B in gonadotrophinomas is confirmed using other techniques, this finding might be important because it was shown that the two isoforms of sst2 receptor mediate opposite effects on cell proliferation: inhibition via sst2A variant and stimulation via sst2B [15]. The data on sst3 receptors in the literature are also divergent.…”

Section: Discussionmentioning

confidence: 95%

Immunohistochemical detection of somatostatin receptor subtypes in “clinically nonfunctioning” pituitary adenomas

et al. 2003

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Pituitary tumors diagnosed before surgery as "non-functioning" in fact represent a heterogenous group, the majority of which express glycoprotein hormones or their free subunits. It is known that some of them expresses somatostatin receptors, but the data available until now rarely refer to the receptor subtype. Five different subtypes of somatostatin receptors (sst1-5) have been cloned. We studied 18 pituitary tumors diagnosed before surgery as "non-functioning." After the surgery the tumors were immunostained with antibodies against pituitary hormones and alpha subunit as well as with antibodies against the somatostatin receptor proteins 1-5. Thirteen adenomas expressed immunoreactivity for FSH, LH, and/or alpha subunit and were classified as gonadotroph adenomas. The remaining five adenomas were immunonegative for all the examined pituitary hormones and were diagnosed as null cell adenomas. All the adenomas of both the groups showed immunopositivity for at least three receptor subtypes. The strongest immunopositivity was found in both groups with anti-sst1 and anti-sst5 antibodies. The marked immunopositivity was also revealed in both groups with anti-sst2B antibody. On the other hand, the sst2A immunopositivity was weak or absent in a majority of tumors. The main difference between two groups was in the sst4 receptor subtype which was absent in all but two gonadotroph adenomas but present in all but one null cell adenoma. These findings suggest that "non-functioning" pituitary adenomas are potential candidates for therapy with somatostatin analogs targeted mainly to the receptor subtypes 1 and 5.

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Section: Discussionmentioning

confidence: 95%

Immunohistochemical detection of somatostatin receptor subtypes in “clinically nonfunctioning” pituitary adenomas

et al. 2003

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“…Among the ®ve subtypes of somatostatin receptors, sst1, sst2, and sst5 have all been implicated to mediate the antiproliferative effects of somatostatin in vitro [33±35]. More recently, Alderton has demonstrated that somatostatin can inhibit cell proliferation through the sst2a receptor in the rat model [35]. This effect appears to be mediated through the G protein.…”

Section: Discussionmentioning

confidence: 99%

Regression of metastatic carcinoid tumors with octreotide therapy: Two case reports and a review of the literature

Leong

Pasieka

2002

Journal of Surgical Oncology

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Background: The antiproliferative effect of the somatostatin analogue, octreotide, on metastatic carcinoid tumors is poorly understood. Partial tumor regression seen radiogaphically has been reported with the use of octreotide therapy for neuroendocrine tumors. Complete regression of carcinoid tumors is rarely reported. Results: Two patients with metastatic midgut carcinoid tumors were treated with subcutaneous octreotide 300 mg/day for symptomatic control of their carcinoid syndrome before debulking palliative surgery. During the laporatomies, both patients were found to have complete macroscopic regression of the metastastatic lesions that had been identi®ed radiologically before surgery, including liver metastases in one patient and periportal and retrocaval lymph nodes in the other. After surgery, the patients were evaluated every 3 months, and had no detectable disease at 30 and 43 months, respectively. Thirty cases of partial tumor regression with octreotide administered with or without other treatment modalities have been reported in the literature. Most of the patients involved received other treatment modalities. Only one other case reported in the literature showed complete regression with octreotide monotherapy. Conclusions: We report two cases of metastatic midgut carcinoid tumors that demonstrated a signi®cant anti-proliferative response to octreotide monotherapy. Review of the literature failed to identify any speci®c prognostic factors with which the response to octreotide can be predicted. Possible mechanisms for this antiproliferative effect of octreotide on carcinoid tumors are discussed.

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“…Activation of either mouse recombinant sst 2 or sst 5 receptors, however, has been shown to inhibit serum-induced proliferation (17), whereas stimulation of the human recombinant sst 4 receptor type induces proliferation in the absence of other mitogenic agents (18). Interestingly, the recently cloned rat sst 2(b) receptor splice variant has also been shown to induce a proliferative response, in marked contrast to the antiproliferative property mediated by the rat sst 2(a) receptor following recombinant expression in the same host cell line (19).…”

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confidence: 86%

Prolonged Activation of Extracellular Signal-regulated Kinase by a Protein Kinase C-dependent and N17Ras-insensitive Mechanism Mediates the Proliferative Response of Gi/o-coupled Somatostatin sst4 Receptors

Sellers

1999

Journal of Biological Chemistry

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The human sst 4 receptor, recombinantly expressed in Chinese hamster ovary cells, mediates proliferative activity of the peptide hormone somatostatin. This effect was shown to involve activation of pertussis toxin-sensitive G proteins and was inhibited by overexpression of the ␤␥-sequestrant, transducin. Somatostatin-induced proliferation was abolished by the MEK1 inhibitor, PD 98059, whereas the Src inhibitor, PP1, had no effect. A marked increase was observed in the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2) 10 min after sst 4 receptor activation, which was blocked by pertussis toxin, decreased by PP1 and the ␤␥-sequestrant, but unaffected by PD 98059. In contrast, the somatostatin-induced phosphorylation of ERK obtained at 4 h, although sensitive to both pertussis toxin and transducin, was unaffected by PP1 but ablated by PD 98059. Protein kinase C inhibition also abolished this somatostatin-induced sustained phosphorylation of ERK, together with the associated increase in cell proliferation. Expression of dominant negative Ras (N17) failed to significantly reduce the proliferative effect mediated by the sst 4 receptor but markedly attenuated the acute phase of the somatostatin-induced phosphorylation of ERK obtained at 10 min. In contrast, the phosphorylation induced at 4 h was unaffected. We conclude that ERK activation by G i/o -coupled sst 4 receptors involves a Src and Ras-dependent acute phase, but the proliferative response is dependent upon the prolonged ERK-induced activity, mediated by protein kinase C.

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Rat somatostatin sst_2(a) and sst_2(b) receptor isoforms mediate opposite effects on cell proliferation

Cited by 19 publications

References 15 publications

Immunohistochemical detection of somatostatin receptor subtypes in “clinically nonfunctioning” pituitary adenomas

Immunohistochemical detection of somatostatin receptor subtypes in “clinically nonfunctioning” pituitary adenomas

Regression of metastatic carcinoid tumors with octreotide therapy: Two case reports and a review of the literature

Prolonged Activation of Extracellular Signal-regulated Kinase by a Protein Kinase C-dependent and N17Ras-insensitive Mechanism Mediates the Proliferative Response of Gi/o-coupled Somatostatin sst4 Receptors

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Rat somatostatin sst2(a) and sst2(b) receptor isoforms mediate opposite effects on cell proliferation

Cited by 19 publications

References 15 publications

Immunohistochemical detection of somatostatin receptor subtypes in “clinically nonfunctioning” pituitary adenomas

Immunohistochemical detection of somatostatin receptor subtypes in “clinically nonfunctioning” pituitary adenomas

Regression of metastatic carcinoid tumors with octreotide therapy: Two case reports and a review of the literature

Prolonged Activation of Extracellular Signal-regulated Kinase by a Protein Kinase C-dependent and N17Ras-insensitive Mechanism Mediates the Proliferative Response of Gi/o-coupled Somatostatin sst4 Receptors

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Rat somatostatin sst_2(a) and sst_2(b) receptor isoforms mediate opposite effects on cell proliferation