Pituitary Adenylate-Cyclase-Activating Polypeptide (PACAP) Binding Sites and PACAP/Vasoactive Intestinal Polypeptide Receptor Expression in Human Pituitary Adenomas

Oka, Hiroyuki; Jin, Long; Reubi, Jean Claude; Qian, Xiang; Scheithauer, Bernd W.; Fujii, Kiyotaka; Kameya, Toru; Lloyd, Ricardo V.

doi:10.1016/s0002-9440(10)65693-3

Cited by 27 publications

(17 citation statements)

References 48 publications

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“…PACAP receptors types I and II have already been shown to be present in somatotroph adenomas (34). However, only in one out of four adenoma cell cultures did PACAP stimulate IL-6 production, which suggests that IL-6 might be enhanced by PACAP in only a small subset of the somatotroph adenomas.…”

Section: Discussionmentioning

confidence: 85%

Functional in vitro studies on the role and regulation of interleukin-6 in human somatotroph pituitary adenomas

et al. 2003

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Objective: Interleukin-6 (IL-6), a member of the gp130 cytokine family, is considered to be an important modulator of function and growth in endocrine anterior pituitary cells. In pituitary adenomas, where IL-6 is often produced by the tumour cells, it is thought to be involved in pituitary adenoma pathophysiology via autocrine/paracrine mechanisms. Methods: We have studied in primary cell cultures of human somatotroph adenomas whether IL-6 stimulates growth hormone secretion and whether intratumoral IL-6 is affected by various IL-6-regulating factors.Results: Interleukin-6 stimulated GH secretion in 10 out of 11 somatotroph adenoma cultures (1.4-to 6.5-fold above basal levels). In comparative studies the GH-stimulatory potency of IL-6 was identical, or even stronger, than that of GHRH. In eight out of 11 adenoma cell cultures, IL-6 production was observed. This suggests that GH production might be stimulated by IL-6 in an autocrine/paracrine manner in these tumours. Dexamethasone strongly inhibited basal IL-6 secretion in all IL-6-producing adenoma cell cultures, whereas the IL-6 inhibitory or stimulatory action of other factors (octreotide, transforming growth factor-b1, insulin-like growth factor-I, pituitary adenylate cyclase-activating peptide and oestradiol) were heterogeneous in the different adenomas. Only transforming growth factor-a consistently stimulated IL-6 secretion in all of the adenomas studied. Conclusions: Intratumoral IL-6, which is differently regulated by various factors, might contribute to excessive GH production in the majority of somatotroph adenomas.

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Section: Discussionmentioning

confidence: 85%

Functional in vitro studies on the role and regulation of interleukin-6 in human somatotroph pituitary adenomas

et al. 2003

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“…This idea is supported by the findings that 1) PACAP neurons are located in the paraventricular and supraoptic nuclei of the hypothalamus (37), 2) PACAP nerve terminals are present in the external zone of the median eminence (38), 3) PACAP immunoreactivity can be detected in the hypophysial portal blood at a level higher than that of systemic circulation (39), and 4) PACAP, under certain conditions, can induce GH, PRL, LH, and ACTH secretion at the pituitary cell level (40). Although the GH-releasing effect of PACAP is still controversial, PACAP receptors have been identified in rat somatotrophs (41,42), somatotroph cell lines (43), and GH-secreting pituitary adenomas (44,45). In the cases of a stimulatory action, the GH-releasing effect of PACAP is either weak (40) or modest (46), susceptible to receptor desensitization (47), and mediated through VPAC 2 receptors (48).…”

Section: Discussionmentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) as a Growth Hormone (GH)-Releasing Factor in Grass Carp. I. Functional Coupling of Cyclic Adenosine 3′,5′-Monophosphate and Ca2+/Calmodulin-Dependent Signaling Pathways in PACAP-Induced GH Secretion and GH Gene Expression in Grass Carp Pituitary Cells

Wong¹,

Li²,

Leung³

et al. 2005

Endocrinology

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Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the glucagon/secretin peptide family, has been recently proposed to be the ancestral GH-releasing factor. Using grass carp as a model for bony fish, we examined the mechanisms for PACAP regulation of GH synthesis and secretion at the pituitary level. Nerve fibers with PACAP immunoreactivity were identified in the grass carp pituitary overlapping with the distribution of somatotrophs. At the somatotroph level, PACAP was shown to induce cAMP synthesis and Ca(2+) entry through voltage-sensitive Ca(2+) channels (VSCC). In carp pituitary cells, PACAP but not vasoactive intestinal polypeptide increased GH release, GH content, total GH production, and steady-state GH mRNA levels. PACAP also enhanced GH mRNA stability, GH promoter activity, and nuclear expression of GH primary transcripts. Increasing cAMP levels, induction of Ca(2+) entry, and activation of VSCC were all effective in elevating GH secretion and GH mRNA levels. PACAP-induced GH secretion and GH mRNA expression, however, were abolished by inhibiting adenylate cyclase and protein kinase A, removing extracellular Ca(2+) or VSCC blockade, or inactivating calmodulin (CaM)-dependent protein kinase II (CaM kinase II). Similar sensitivity to VSCC and CaM kinase II blockade was also observed by activating cAMP production as a trigger for GH release and GH gene expression. These results suggest that PACAP stimulates GH synthesis and secretion in grass carp pituitary cells through PAC(1) receptors. These stimulatory actions probably are mediated by the adenylate cyclase/cAMP/protein kinase A pathway coupled to Ca(2+) entry via VSCC and subsequent activation of CaM/CaM kinase II cascades.

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“…The presence of type II recognition sites also occurs in human pituitary adenoma (Robberecht et al, 1993;Oka et al, 1998) and brain glioma Vertongen et al, 1995a;Sokolowska and Nowak, 2006). 308 Therefore, attempts have been made to use PACAP or VIP radioligands to localize tumor cells by scintigraphy in various tissues Raderer et al, 1998;Virgolini et al, 1998;Reubi, 2000;Igarashi et al, 2005;Zhang et al, 2007a), and VIP derivatives mixed with nanomicelles are currently developed as a possible delivery platform to target breast cancer cells (Ashok et al, 2004;Rubinstein et al, 2008;Onyü ksel et al, 2009a,b).…”

Section: G Pituitary Adenylate Cyclase-activating Polypeptide Receptmentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

et al. 2009

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Pituitary Adenylate-Cyclase-Activating Polypeptide (PACAP) Binding Sites and PACAP/Vasoactive Intestinal Polypeptide Receptor Expression in Human Pituitary Adenomas

Cited by 27 publications

References 48 publications

Functional in vitro studies on the role and regulation of interleukin-6 in human somatotroph pituitary adenomas

Functional in vitro studies on the role and regulation of interleukin-6 in human somatotroph pituitary adenomas

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

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