Neurotensin (NTS) binds to the G protein-coupled receptors (GPCRs) NTSR1 and NTSR2. NTSR1 regulates transactivation of the EGFR, HER2, and HER3, but its effects on HER4 are unknown. By Western blot, NTSR1 and HER4 were present in six lung cancer cell lines examined. In NCI-H522 or NCI-H661 cells, adding NTS increased phosphorylation (P) of tyrosine (Y) 1284 on HER4. Because SR48692 antagonized NTS’s ability to increase P-HER4 or P-ERK, NTSR1 may play an important role in NSCLC. SR48692, HER4 siRNA, reactive oxygen species inhibitors, and the tyrosine kinase inhibitor ibrutinib inhibited NTS-induced P-HER4. Adding NTS to NCI-H661 cells increased the formation of HER4/HER4, HER4/ EGFR, and HER4/HER2 dimers. Adding NTS to NSCLC cells increased both P-ERK and P-AKT, which were inhibited by PD98059 and LY294002, respectively. The growth of NCI-H522 or NCI-H661 cells was stimulated by NTS or neuregulin 1 (NRG1), a HER4 ligand, but inhibited by SR48692 or ibrutinib. The results indicate that NTSR1 regulates HER4 transactivation, thereby increasing the proliferation of lung cancer cells.

Serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A) play important roles in mediating cellular signaling in different tissues to different stimuli, including in protein synthesis, growth, cell cycle regulation, and secretion. However, their roles in various pancreatic exocrine functions, such as pancreatic acinar fluid/electrolyte secretion, is still unclear. Therefore, in the present study, we examined the ability of vasoactive intestinal peptide (VIP) and secretin, which stimulate cAMP generation in pancreatic acini, to activate serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A), the signaling cascades involved, and their possible role in activating sodium-potassium adenosine triphosphatase (Na+-K+-ATPase). Our results demonstrate that VIP and secretin activate PP1 and PP2A. However, they differ in their signaling cascades. Both VIP and secretin stimulate PP1 through cAMP-stimulated activation of protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC). However, VIP stimulates PP2A through the activation of cAMP-mediated EPAC, whereas secretin does it through activation of PKA. Despite these differences, in cAMP effect on activation, both VIP and secretin activate PP2A through a p21-activated kinase 4 (PAK4)-mediated mechanism, without involvement of PAK2. Furthermore, PP1 and PP2A activation is needed for Na+-K+-ATPase activation, which mediates pancreatic acinar fluid and electrolyte secretion. These results support the conclusion that PP1 and PP2A play an important role in pancreatic acinar fluid and electrolyte secretion, mediated by a PAK4-dependent mechanism, which when combined with their recently described roles in pancreatic enzyme secretion, pancreatitis, and pancreatic acinar growth and cancer, demonstrate the important roles they play in both physiological and pathological responses in the exocrine pancreas, similar to their previously established roles in the endocrine pancreas.NEW & NOTEWORTHY The roles of the serine/threonine phosphatase 1/2A in mediating fluid/electrolyte secretion by pancreatic acinar cells remains unclear. This study demonstrates that PP1/PP2A are activated vasoactive intestinal peptide (VIP)/secretin in pancreatic acini. VIP/secretin both activate PP1/PP2A but differed for their ability to activate exchange protein directly activated by cAMP (EPAC) and protein kinase A (PKA). VIP/secretin require PAK4, not PAK2, activation to stimulate PP2A, not PP1; however, PP1/PP2A activation stimulate sodium-potassium adenosine triphosphatase (Na+-K+-ATPase) activity. This study shows that PP1/PP2A play important roles in VIP-secretin-stimulated pancreatic acinar fluid/electrolyte secretion.

Bombesin receptor subtype-3 (BRS-3) is a type 1 G-protein-coupled receptor (GPCR). BRS-3 is an orphan GPCR that is structurally related to neuromedin B and gastrin-releasing peptide receptors. When activated, BRS-3 causes phosphatidylinositol turnover in lung cancer cells. BRS-3 stimulates tyrosine the phosphorylation of the epidermal growth-factor receptor (ErbB1); however, it is unknown whether it transactivates ErbB2/HER2. Adding the nonpeptide BRS-3 allosteric agonist MK-5046 or the peptide agonist BA1 to the lung cancer cell line NCI-H727 or to BRS-3-transfected NCI-H1299 lung cancer cells increased the tyrosine phosphorylation of HER2/ERK2. This increase was antagonized by the BRS-3 peptide antagonist Bantag-1 and the small-molecule BRS-3 antagonist ML-18. The increase in HER2/ERK phosphorylation caused by MK-5046 was inhibited by the ROS inhibitors N-acetylcysteine and Tiron (superoxide scavengers). Adding MK-5046 to lung cancer cells increased reactive oxygen species, which was inhibited by NAC or Tiron. MK-5046 and BA1 increased non-small lung cancer cell (NSCLC) colony formation, whereas Bantag-1/ML-18 inhibited proliferation. These results indicate that in lung cancer cells, the activation of BRS-3 regulates HER2 transactivation in an ROS-dependent manner, which can mediate tumor growth. These results raise the possibility that the use of HER2-inhibiting compounds alone or in combination with other agents could represent a novel approach to the treatment of these tumors.

Serine/threonine phosphatases, protein phosphatases 1 and 2A (PP1 and PP2A), play important roles in mediating cellular signaling in different tissues to different stimuli, including glycogen metabolism, protein synthesis/growth, and secretion. However, the roles of PP1/PP2A in pancreatic acinar cell secretion/growth are both unclear and controversial. To address this issue, in the present study, we examined the ability of gastrointestinal hormones/growth factors (GFs) to activate PP1 and PP2A and the signaling cascades involved in rat pancreatic acini and the pancreatic acinar tumor cell line, AR42J cells. PP1 and PP2A were both detected in pancreatic acini and AR42J cells. In acini, PP1 and PP2A were activated by pancreatic secretagogues-stimulating phospholipase C (bombesin, CCK-8, and carbachol) and endothelin and by pancreatic GFs (insulin, hepatocyte growth factor, epidermal growth factor, basic fibroblast growth factor, platelet-derived growth factor, and insulin-like growth factor 1). Full CCK-8 activation of PP1/PP2A required activation of both high- and low-affinity CCK1-receptor states. Using specific PP1 and PP2 assays, in both acini and AR42J cells, experimental conditions were established, where calyculin A, a known nonselective PP1/PP2A inhibitor, inhibited activation of both, whereas okadaic acid and fostriecin inhibited only PP2A activation and tautomycetin inhibited only PP1 activation. Under these conditions, CCK-stimulated enzyme secretion and stimulation of p44/42, a key mediator of growth, required PP2A activation, without activation of PP1. Using specific siRNA for PP1/PP2A in AR42J cells, similar results were found. These results establish that only PP2A activation is essential for CCK-mediated stimulation of growth and enzyme secretion in pancreatic acinar cells and pancreatic acinar AR42J tumor cells.NEW & NOTEWORTHY Despite more than 10 studies, the roles of the serine/threonine phosphatases, PP1/PP2A, in pancreatic acinar cell-secretion/growth remain controversial. This study demonstrates that both PP1/PP2A are present in rat pancreatic acini and in pancreatic acinar tumor-AR42J cells. Both phosphatases are activated by pancreatic secretagogues, stimulating PLC, and by pancreatic growth factors. Using specific inhibitory conditions for PP1/PP2A (inhibitors, siRNA studies), only PP2A activation is needed for CCK-8-stimulated enzyme secretion and growth signaling cascades in pancreatic acinar cells.

Gastrointestinal neuroendocrine tumor (GI NET) syndromes are clinical syndromes caused by the release of biologically active peptides/amines by GI neuroendocrine tumors. NETs comprise carcinoid tumors and pancreatic endocrine tumors and are derived from amine- and peptide-producing cells of the diffuse neuroendocrine system.

The bombesin (Bn) receptor family [Gastrin-releasing peptide (GRPR/BB2R) and Neuromedin B receptors (NMBR/BB1R)] are G-protein coupled receptors (GPCR’s) with potent growth effects on normal tissues/numerous cancers, often by transactivating the ErbB receptor-tyrosine kinase (RTK) family. Whereas GRPR stimulation transactivates ErbB RTKs EGFR, HER2, and HER3 in non-small cell lung-cancer (NSCLC) cells, its effects on HER4 are unknown. This study was designed to address this question. Of 12 NSCLC’s studied, 75% had HER4 mRNA expression and Western-Blotting. NCI-H522 and NCI-H661-cells had high levels of GRPR, HER4, and the HER4-ligand neuregulin (NRG1). Adding GRP to NCI-H522/NCI-H661-cells activated HER4, shown by its increased phosphorylation (P-HER4). The GRPR antagonists PD176252/BW2258U89 inhibited this increase. In NCI-H661-cells, GRP stimulated the formation of HER4-homodimers and HER2-HER4-heterodimers. Adding GRP to these NSCLC-cells increased P-ERK/P-AKT, which was inhibited by siRNA-HER4, PD176252, and ibrutinib, as well as N-acetylcysteine and Tiron, which reduce reactive-oxygen species (ROS). GRP increased secretion of NRG1 from NSCLC-cells, and NRG1 increased P-HER4 and P-ERK, which were impaired by ibrutinib. GRP and NRG1 stimulated proliferation of NSCLC-cells, which was inhibited by PD176252, siRNA-HER4, or ibrutinib and which was mediated by MAPK, not AKT/PI3K, activation. These results show GRPR activation results in HER4 transactivation in a ROS-dependent manner, which stimulates NSCLC-growth through a MAPK-mediated mechanism.

Purpose: Zollinger–Ellison syndrome (ZES) is the most frequent, functional, malignant pancreatic neuroendocrine tumor syndrome (pNET), which is due to ectopic secretion of gastrin by a pNET/NET (i.e., gastrinomas) resulting in severe, refractory acid-peptic disease (ulcer, GERD). ZES has several unique management features, which lead to a number of unresolved controversies. Areas covered: Whereas both medical and surgical controversies exist, they have not been examined in detail for some time. This review contains an analysis of a number of the main current, medical controversies that are unresolved in ZES patients, including insights into the basis of these controversies and possible insights into their resolution from recent studies in patients with gastrinomas or from recent studies in other pNET syndromes or other neuroendocrine tumors (NETs). These include the following: controversies in the long-term control of acid secretion and acid antisecretory drug side-effects; controversies related to the difficulty in making the diagnosis of ZES; nonsurgical MEN1/ZES controversies related to the management of gastric carcinoids (Type II); nonsurgical MEN1/ZES controversies related to whether genotype–phenotype correlations exist in MEN1 patients including MEN1/ZES patients; nonsurgical MEN1/ZES controversies related to the roles of imaging/tumor localization in MEN1 patients for gastrinomas/pNETs in their initial/follow-up management; controversies related to the role of non-surgical tumor ablation for treatment of ZES/gastrinomas; and controversies related to medical treatment selection for advanced, metastatic disease in patients with ZES/gastrinomas/other malignant pNETs. Conclusions: In this paper, the basis for the development of each of these unique ZES-related controversies is discussed and insights into progress that could lead to their resolution are reviewed.

The p21-activated kinases (PAKs) are a conserved family of serine/threonine protein kinases, which are effectors for the Rho family GTPases, namely, Rac/Cdc42. PAKs are divided into two groups: group I (PAK1–3) and group II (PAK4–6). Both groups of PAKs have been well studied in apoptosis, protein synthesis, glucose homeostasis, growth (proliferation and survival) and cytoskeletal regulation, as well as in cell motility, proliferation and cycle control. However, little is known about the role of PAKs in the secretory tissues, including in exocrine tissue, such as the exocrine pancreas (except for islet function and pancreatic cancer growth). Recent studies have provided insights supporting the importance of PAKs in exocrine pancreas. This review summarizes the recent insights into the importance of PAKs in the exocrine pancreas by reviewing their presence and activation; the ability of GI hormones/neurotransmitters/GFs/post-receptor activators to activate them; the kinetics of their activation; the participation of exocrine-tissue PAKs in activating the main growth-signaling cascade; their roles in the stimulation of enzyme secretion; finally, their roles in pancreatitis. These insights suggest that PAKs could be more important in exocrine/secretory tissues than currently appreciated and that their roles should be explored in more detail in the future.

Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [197], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [153]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.Table 1: Class A orphan GPCRs with putative endogenous ligands GPR3GPR4GPR6GPR12GPR15GPR17GPR20 GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GPR65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well-structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point-in-time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70230. The Concise Guides provide expert-curated recommendations of 'Gold Standard' selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid-2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. Each section includes nomenclature guidance, concise summaries, information of the best available pharmacological tools, key references, and suggestions for further reading.

Mammalian bombesin (Bn) receptors comprise 3 subtypes: BB1, BB2, BB3 (nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors, [118, 5]). BB1 and BB2 are activated by the endogenous ligands neuromedin B (NMB), gastrin-releasing peptide (GRP), and GRP-(18-27). bombesin is a tetra-decapeptide, originally derived from amphibians and structurally closely related to GRP. The three Bn receptor subtypes couple primarily to the Gq/11 and G12/13 family of G proteins [118]. Each of these receptors is widely distributed in the CNS and peripheral tissues [81, 118, 259, 288, 373, 115, 6, 375, 125, 204]. Activation of BB1 and BB2 receptors causes a wide range of physiological/pathophysiogical actions, including the stimulation of normal and neoplastic tissue growth, smooth-muscle contraction, respiration, gastrointestinal motility, feeding behavior, secretion and many central nervous system effects including regulation of circadian rhythm, body temperature control, sighing, behavioral disorders and mediation of pruritus [210, 118, 204, 259, 211, 37, 375, 211, 44, 4]. BB3 is an orphan receptor, although some propose it is constitutively active [328]. BB3 receptor knockout studies show it has important roles in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [154, 81, 223, 208, 4, 208]. Bn receptors are one of the most frequently overexpressed receptors in cancers and are receiving increased attention for their roles in tumor growth, as well as for tumour imaging and for receptor-targeted cytotoxicity especially for advanced prostate and breast cancer [210, 167, 13, 136, 377, 371]. Bn receptors are also receiving attention because they are one of the primary neurotransmitters for pruritus [37, 128, 240].

Gastrinomas secrete gastrin and cause symptoms related to gastric acid hypersecretion that can be controlled by antisecretory medications. Primary tumors are located within the pancreas or duodenum and 60% metastasize. Liver metastases are associated with decreased survival. Localization studies especially somatostatin receptor scintigraphy are indicated to image the extent of disease. Surgery is indicated to potentially cure the patient, or control the malignant tumoral process and prolong survival.

Abstract The neurotensin receptor 1 (NTSR1) is a 418 amino acid type A G protein-coupled receptor which causes phosphatidylinositol turnover and proliferation of non-small cell lung cancer (NSCLC) cells (Moody et al., Peptides 2021; 137: 710480). Adding the agonist NTS to NSCLC cells increases transactivation of the receptor tyrosine kinases (RTK) EGFR, HER2 and HER3 (Moody et al., Biology 2023 12: 957). The RTK tyrosine phosphorylation and growth caused by NTS is impaired by SR48692, a small molecule NTSR1 antagonist. The effects of NTS were investigated on HER4 using NSCLC cells. By Western blot, cell lines NCI-H522 and H661 had high levels of NTSR1, HER 4 and neuregulin 1 (NRG1), a ligand for HER4 but not NTSR2, HER3 or NRG2. By RT-PCT, high levels of HER4 and its isoforms JM-a, CYT1 and CYT2 were present in NCI-H522 and H661 cells. Adding NTS (0.1 μM) or NRG1 (0.01 μg/ml) to NCI-H522 or H661 cells increased P-Tyr1284-HER4 and P-ERK 3-fold. Using immunoprecipitation techniques, adding NTS to NSCLC cells increased formation of HER4-HER2 heterodimers which leads to cancer proliferation (Lucas et al., Pharmacol Rev 2022; 74:18). The increase in PY1284-HER4 caused by NTS was impaired by SR48692, HER4 siRNA, NRG1 siRNA or ibrutinib (TKI). The NTSR1 regulation of HER4 transactivation is impaired by GM6001 (MMP inhibitor]), PP2 (Src inhibitor) or N-acetylcysteine (antioxidant). The clonal growth of NSCLC cells is increased by NTS or NRG1 but decreased by SR48692 or ibrutinib. The results indicate that NTS increases the formation of HER2/HER4 heterodimers leading to the proliferation of NSCLC cells. Citation Format: Terry W. Moody, Irene Ramos-Alvarez, Robert T. Jensen. Neurotensin receptor 1 regulates dimerization of HER2-HER4 and proliferation of non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6266.

Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger–Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency.

The ErbB RTKs (EGFR, HER2, HER3, and HER4) have been well-studied in cancer. EGFR, HER2, and HER3 stimulate cancer proliferation, principally by activating the phosphatidylinositol-3-kinase and extracellular signal-regulated kinase (ERK) pathways, resulting in increased cancer cell survival and proliferation. Cancer cells have high densities of the EGFR, HER2, and HER3 causing phosphorylation of tyrosine amino acids on protein substrates and tyrosine amino acids near the C-terminal of the RTKs. After transforming growth factor (TGF) α binds to the EGFR, homodimers or EGFR heterodimers form. HER2 forms heterodimers with the EGFR, HER3, and HER4. The EGFR, HER2, and HER3 are overexpressed in lung cancer patient tumors, and monoclonal antibodies (mAbs), such as Herceptin against HER2, are used to treat breast cancer patients. Patients with EGFR mutations are treated with tyrosine kinase inhibitors, such as gefitinib or osimertinib. Peptide GPCRs, such as NTSR1, are present in many cancers, and neurotensin (NTS) stimulates the growth of cancer cells. Lung cancer proliferation is impaired by SR48692, an NTSR1 antagonist. SR48692 is synergistic with gefitinib at inhibiting lung cancer growth. Adding NTS to lung cancer cells increases the shedding of TGFα, which activates the EGFR, or neuregulin-1, which activates HER3. The transactivation process is impaired by SRC, matrix metalloprotease, and reactive oxygen species inhibitors. While the transactivation process is complicated, it is fast and occurs within minutes after adding NTS to cancer cells. This review emphasizes the use of tyrosine kinase inhibitors and SR48692 to impair transactivation and cancer growth.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Introduction: The actin regulatory protein, cofilin plays a key signaling role in many cells for numerous cellular responses including in proliferation, development, motility, migration, secretion and growth. In the pancreas it is important in islet insulin secretion, growth of pancreatic cancer cells and in pancreatitis. However, there are no studies on its role or activation in pancreatic acinar cells.Methods: To address this question, we studied the ability of CCK to activate cofilin in pancreatic acinar cells, AR42J cells and CCK1-R transfected Panc-1 cells, the signaling cascades involved and its effect on enzyme secretion and MAPK activation, a key mediator of pancreatic growth.Results: CCK (0.3 and 100 nM), TPA, carbachol, Bombesin, secretin and VIP decreased phospho-cofilin (i.e., activate cofilin) and both phospho-kinetic and inhibitor studies of cofilin, LIM kinase (LIMK) and Slingshot Protein Phosphatase (SSH1) demonstrated these conventional activators of cofilin were not involved. Serine phosphatases inhibitors (calyculin A and okadaic acid), however inhibited CCK/TPA-cofilin activation. Studies of various CCK-activated signaling cascades showed activation of PKC/PKD, Src, PAK4, JNK, ROCK mediated cofilin activation, but not PI3K, p38, or MEK. Furthermore, using both siRNA and cofilin inhibitors, cofilin activation was shown to be essential for CCK-mediated enzyme secretion and MAPK activation.Conclusion: These results support the conclusion that cofilin activation plays a pivotal convergent role for various cell signaling cascades in CCK mediated growth/enzyme secretion in pancreatic acini.

Neuroendocrine neoplasm (NEN) is a collective term that refers to tumors originating in neuroendocrine cells that arise in various organs of the body. NENs comprise a heterogeneous group of neoplasms with a wide spectrum of clinical and malignant behaviors depending on various clinicopathologic factors. While pancreatic NEN (PanNEN) are relatively rare, an epidemiologic study revealed that their incidence is increasing. PanNEN is considered a malignant tumor due to its metastatic potential, although its progression is slow. PanNEN is classified into well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC). Accurate diagnosis is necessary because the treatments of NET and NEC are completely different. Further, pancreatic NET (PanNET) is broadly classified into functional PanNET, which is associated with excessive hormone secretion, and nonfunctional PanNET, which does not exhibit hormone secretion. Functional PanNET is characterized by hormone-derived specific clinical manifestations, while nonfunctional PanNET is often asymptomatic. Therefore, nonfunctional PanNET is frequently found only after tumor growth or metastasis. For clinical purposes, accurate localization of the tumor is as important as detecting its presence. In this chapter, the clinical manifestation of the different types of PanNET will be considered as well as aspects of their diagnosis of the hormone excess state.

Pituitary adenylate cyclase activating polypeptide [PACAP] is a 27 amino acid peptide which stimulates the growth of numerous cancers including non-small cell lung cancer (NSCLC). PACAP binds with high affinity to the type B G protein-coupled receptor [GPCR] PAC1 (Moody et al., Peptides 2021; 137: 170480). PAC1 activation causes phosphatidyl inositol [PI] turnover stimulating matrix metalloprotease [MMP]. By ELISA, PACAP increased secretion of neuregulin [NRG1] from NSCLC cells. NRG1 binds with high affinity to HER4. Here the ability of PAC1 to regulate transactivation of HER4 was investigated. By RT-PCR and Western blot, PAC1, NRG1 and HER4 but not HER3 or NRG2 were detected in NCI-H522 and H661 cells. Adding PACAP-27 (0.1 μM) or NRG1 (0.01 μg/ml) to NCI-H522 or H661 cells increased P-Tyr1284-HER4 3-fold after 5 min. Using immunoprecipitation techniques, adding PACAP TO NSCLC cells increased formation of HER4 homodimers and HER4-EGFR as well as HER4-HER2 heterodimers. The increase in P-HER4 caused by PACAP-27 was impaired by PACAP(6-38) [PAC1 antagonist], HER4 siRNA, NRG1 antibody [Ab] or ibrutinib [TKI]. The PAC1 regulation of HER4 transactivation is impaired by GM6001 [MMP inhibitor]. The clonal growth of NSCLC cells was stimulated by PACAP-27 or NRG1 but inhibited by PACAP(6-38) or ibrutinib. The results indicate that PACAP-27 stimulates the growth of NSCLC due to release of NRG1 which activates receptor tyrosine kinases such as HER4. Citation Format: Terry W. Moody, Irene Ramos Alvarez, Robert T. Jensen. Pituitary adenylate cyclase activating polypeptide stimulates NSCLC growth by increasing HER4 tyrosine phosphorylation in a neuregulin-1 dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3071.

Analysis of the efficacy/pharmacology of long-term/lifetime medical treatment of acid hypersecretion in a large cohort of ZES patients in a prospective study. This study includes the results from all 303 patients with established ZES who were prospectively followed and received acid antisecretory treatment with either H2Rs or PPIs, with antisecretory doses individually titrated by the results of regular gastric acid testing. The study includes patients treated for short-term periods (<5 yrs), patients treated long-term (>5 yrs), and patients with lifetime treatment (30%) followed for up to 48 years (mean 14 yrs). Long-term/lifelong acid antisecretory treatment with H2Rs/PPIs can be successfully carried out in all patients with both uncomplicated and complicated ZES (i.e., with MEN1/ZES, previous Billroth 2, severe GERD). This is only possible if drug doses are individually set by assessing acid secretory control to establish proven criteria, with regular reassessments and readjustments. Frequent dose changes both upward and downward are needed, as well as regulation of the dosing frequency, and there is a primary reliance on the use of PPIs. Prognostic factors predicting patients with PPI dose changes are identified, which need to be studied prospectively to develop a useful predictive algorithm that could be clinically useful for tailored long-term/lifetime therapy in these patients.