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Biochemistry, Bombesin
Introduction
Bombesin (BBS, BB), is a 14-amino acid neurohormone polypeptide, derived initially from amphibians with a wide range of physiological effects in the brain, lungs, and GI tract. Bombesin regulates gastrointestinal hormone release and gastrointestinal motility.[1] Recently, studies have evaluated the role of bombesin in tumor growth, cellular proliferation, and inflammation.[2] Research has also discovered several peptides structurally related to bombesin.[3] Two well-studied homologs are called neuromedin B and gastrin-releasing peptide (GRP).[1] The gastrin-releasing peptide is biologically and immunologically equivalent to bombesin, making GRP the mammalian equivalent. In addition to gastric neurohormonal impacts on the GI tract, the BN-like peptides have also been shown to modulate satiety, thermoregulation, glucose homeostasis, and circadian rhythms.[4][5]
Fundamentals
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Fundamentals
Bombesin receptors (BBR) are G-protein-coupled receptors. These receptors classify into three different types.
- Neuromedin-B receptor ([NMB] also known as bombesin receptor 1 [BRS1, BB1, BBR-1])
- Gastrin-releasing peptide receptor ([GRPR] also known as bombesin receptor 2 [BRS1, BB2, BBR-2]).
- GRPR is expressed in the pancreas and at lower levels in the colon, breast, prostate, and skin.
- Bombesin binding sites in the pancreas have a higher affinity for GRP and bombesin than compared to its other analog neuromedin B. This compares to the bombesin binding sites in the esophagus, which have a higher affinity to neuromedin B and bombesin than compared to GRP; this suggests that although bombesin has mammalian analogs, their true functions are not identical. The GRP-preferring binding sites were called "BB2" while the NMB-preferring binding sites were called "BB1". GRP has a higher affinity for BBR-2 than for BBR-1, making it a promising target for directed cancer therapies.[6]
- Orphan receptor ([OR], also known as bombesin receptor 3 [BRS3, BB3, or BBR-3]).[7]
Bombesin has no known antagonist capability (i.e., receptor blocking effects). The area of the bombesin molecule that controls essential physiological activity also determines the affinity of the peptide toward its receptors. That is, the difference in potency amongst various derivatives and analogs of bombesin correlates with the variety in their receptor affinities. Of the segments and analogs of bombesin examined, none have been observed to occupy the bombesin receptor without causing a full biological response. Therefore, there remain no bombesin-related peptides that operate as a bombesin receptor antagonist.
As a stimulatory peptide, bombesin's effects do have variable potency in their impacts. The essential physiological effect of bombesin-related peptides is attributed to the carboxy-terminal portion of the molecule.[11][12] Shortened carboxy-terminal variants of bombesin still maintain full inherent biological response, but their influences are less than that of primary bombesin.[11][12][13][14] Bombesin receptors (and their analogs) are found in higher prevalence within breast, colon, lung, ovarian, urinary bladder, skin, and prostate tumors. Knowing this, researchers have attempted to target these receptors by using synthetic analogs of bombesin that are modified to contain chemotherapy agents (i.e., targeted chemotherapy).
Issues of Concern
It bears mentioning that bombesin is not structurally compatible with the biochemical processes because radioactive iodine (i.e., needed for biotech processes) normally binds to a tyrosine residue on the peptide of interest. Bombesin’s primary structure conflicts with the radioactive iodine and hence renders bombesin incapable of creating a radioactive peptide. This fact is important because the radioactive peptide is what researchers use for receptor binding studies. This issue is also true of all peptides structurally related to bombesin, thus potential use in radioactive labeling may not be possible.[15][16]
Cellular Level
Bombesin binds to G protein-coupled receptors, which stimulate adenylate cyclase, increasing intracellular cyclic adenine monophosphate (cAMP) levels and activating intracellular signal cascades. These cascades propagate, leading to calcium, sodium, and potassium fluxes inducing the modulation of growth factor receptors, and expression of the proto-oncogenes c-fos and c-myc.[17]. When bound to G-cells, bombesin signal transduction ultimately produces phosphatidylinositol, which acts as a secondary messenger, mediating intracellular vesicular fusion with the plasma membrane, and therefore regulating gastrin secretion from G-cells in the antrum of the stomach.[18][19]
Bombesin G protein-coupled receptor signal-cascade also results in the activation of protein kinase C (PKC) through the phosphatidylinositol second-messenger system.[17] Bombesin and bombesin-like peptides can activate protein kinase C proteins by endogenous diacylglycerol(DAG) levels; this increases the synthesis of cellular cyclic guanosine monophosphate (cGMP) molecules enabling the mobilization of intracellular calcium. Intracellular calcium activates the intracellular signal cascade mechanism controlling hormone secretion.[6]
Bombesin-associated extracellular events include stimulation of mitogenesis and monocyte chemoattraction.[20] A study showed evidence of bombesin’s mitogenic capabilities was whereby vasopressin caused desensitization to the mitogenic action of bombesin mediated by uncoupling the receptor from its signaling system.[17][20] Therefore the localization of these receptors is preassumed to be positioned on the basolateral side of the cell plasma membrane. There remain no studies that have localized receptors for bombesin or structurally associated peptides.
Function
In the brain, bombesin is known as neuromedin B and is involved in smooth muscle contraction.[21] Bombesin is present in regions of the trachea, bronchus, and within the whole lung at different stages of human fetal development. Bombesin is present in neonates, children, and adults.[22]
Bombesin causes the release of endogenous gastrin, activating sensory neurons located in the gastric fundus responsible for gastric smooth muscle motility and luminal protection. Activation of sensory neurons causes increased production of nitric oxide through activation of constitutive nitric oxide synthase. Activation of nitric oxide synthase leads to an increase in gastric mucosal blood flow and makes the stomach less susceptible to injury from luminal irritants.[23] Bombesin is the most effective promotor of G cell-regulated gastrin release plus subsequent stimulation of gastric acid excretion.[16][24][25][24]
Bombesin is predominantly known to regulate homeostasis within the gastrointestinal tract.[1] When binding to gastrointestinal luminal receptors, bombesin produces adverse effects such as nausea, vomiting, and diarrhea. Bombesin is the major source of negative feedback signals that stop eating behavior second only to cholecystokinin.[26]
Bombesin can function as a growth factor through autocrine or paracrine mechanisms, which may modulate the growth of various benign and neoplastic tissues. Therefore, the problem this protein can address is that of prostate precision. The fact that radiolabeling cannot differentiate between benign hyperplastic prostate cells and malignant carcinoma cells limits their diagnostic value. Hence, there has been much effort put into developing new prostate carcinoma–specific PET tracers with high diagnostic sensitivity and specificity.[27][28]
Mechanism
Bombesin binds to the G-protein receptor. G protein-coupled reaction occurs, which activates a phosphorylation cascade. Phosphorylation cascade cleaves PIP2. PIP2 separates into inosine-monophosphate (IP3) and diacylglycerol (DAG). IP3 and DAG both increase in concentration within the cell. DAG interacts with protein kinase C (PKC). DAG-PKC interaction activates protein kinase C (aPKC). aPKC phosphorylates serine residues on intracellular target proteins.[29] Intracellular target proteins release calcium stores intracellularly. Intracellular calcium levels increase, causing cellular depolarization. Intracellular calcium binds to synapsin, altering its conformation. Altered synapsin causes intracellular vesicle diffusion. Altered synapsin exposes calcium-binding sites on microtubules attached to intracellular vesicles. Calcium activates dynein arms causing efferent microtubules diffusion. Vesicles fuse with the plasma membrane and release their contents into the extracellular environment.[29]
Pathophysiology
Researchers believe that neuropeptides influence feeding, satiety, energy homeostasis, and other parameters associated with weight control.[30] Those involved are bombesin, insulin, and orexins. These peptides exhibit diverse effects upon the hypothalamus by acting as ligands for G protein-coupled receptors within the brain. Some tumors can produce agents such as bombesin and adrenocorticotropic hormone, which can affect caloric processing.[31][32][33] The abnormal intake and utilization of calories contribute to the altered metabolism associated with cachexic states precipitated by tumorigenesis, which leads to a cyclical chain of events in which protein catabolism, glucose intolerance, and lipolysis cannot be augmented by the addition of calories.
Inhalational exposures can precipitate an inflammatory reaction within the airways and alveoli, leading to activated neutrophils, and other inflammatory cells release proteases as part of the inflammatory process. Neutrophil-induced oxidative damage stimulates the release of profibrotic neuropeptide bombesin in the normal process of tissue repair. This mechanism appears to contribute to the pulmonary neuroendocrine cells' promotion of bombesin-like peptide immunoreactivity.[34]
Studies have correlated bombesin-like immunoreactivity with the abnormal inflammatory response seen in bronchopulmonary dysplasia.[35][36] Researchers in a study of 132 infants at 28-weeks gestation or less found that bombesin-like peptide levels elevate in the urine prior to the development of bronchopulmonary dysplasia.[37] Infants who had elevated levels of the bombesin-like peptide in their urine 1 to 4 days after birth were ten times more likely to develop bronchopulmonary dysplasia.[37] Therefore, urine bombesin-like peptide screening might allow for early therapeutic interventions to minimize disease progression.
Eosinophilic granuloma is a fibrotic lung disease almost always seen in adult cigarette smokers. One study showed that the number of pulmonary neuroendocrine cells with bombesin-like immunoreactivity increases in patients with eosinophilic granuloma.[20] Therefore neuroendocrine cell hyperplasia may lead to bombesin-like peptide elevation and subsequent monocyte and fibroblast recruitment, which contribute to granuloma formation; this would be in line with other studies which have shown bombesin to be chemotactic for monocytes and mitogenic for fibroblasts.[20]
Inhibition of Ca ++ influx inhibits the release of neurotransmitters like bombesin, acetylcholine, norepinephrine, serotonin, somatostatin, and substance P. These neurotransmitters mediate pain perception in the spinal cord. Inhibition of release into the synaptic cleft leads to decreased postsynaptic neuronal firing and transmission of nociception.[38]
Tumors of neuronal origin such as medulloblastoma, primitive neuroectodermal tumors, neuroblastoma, pineoblastoma are bombesin positive. Recently it has been suggested that bombesin-related peptides are involved in the autocrine stimulation of human small-cell lung carcinomas The growth and metastatic potential of neuroendocrine tumors. The molecular mechanisms and signaling pathways that are responsible for bombesin-like peptide-induced cell migration and invasion remain unclear.[23][39]
Bombesin exerts a stimulatory effect on the growth of human prostatic cancer cells in vitro.[34] Bombesin also has a role in prostatic epithelium growth; this would support other studies stating that prostatic carcinoma may have an endocrine, autocrine, or paracrine proliferation stimulus within the gland microenvironment.[40][41][42] This important fact provides an objective basis for the development of neuropeptides as therapeutic targets and may be helpful in the treatment of advanced prostatic carcinoma.[43][41]
Clinical Significance
Loss of bombesin receptors correlates with age-dependent obesity, hypertension, glucose intolerance, and high insulin levels. This expanded adipose deposition may, in part, be due to a decline in energy consumption without a shift in eating or movement, which infers that bombesin receptors may signify a plausible target upon which notable advancement can take place in the realm of anti-obesity agents.
Bombesin has the theoretical capability to address prostate cancer screening. Current screening methods include prostate-specific antigen serum testing, followed by a digital rectal examination. Those screening techniques do not yield information on the primary location of the carcinoma cells. Therefore, possible metastases cannot be determined or diagnosed with high accuracy. The fact that radiolabeling cannot differentiate between benign hyperplastic prostate cells and malignant carcinoma cells limits their diagnostic value. BBR and gastrin-releasing peptide receptors are over-expressed in solid malignancies and particularly in prostate cancer.[44] These receptors are over-expressed rarely and, if expressed, then only in low density in benign prostatic hyperplasia and normal prostate tissue.[45] Studies have shown that prostate tissue has a high density of receptors belonging to the bombesin receptor family.[46] This finding has sparked an interest in developing new prostate carcinoma–specific PET tracers, which would provide high diagnostic sensitivity and specificity.
Precision medicine is also known as theranostics, is a medical model that separates people into different groups with medical care tailored to the individual patient based on their predicted response or risk of disease.[47] Gastrin-releasing peptide receptor antagonists have promise in theranostics of several highly incident tumors, including prostate and breast.[48] Bombesin receptors often demonstrate significant expression on a variety of tumors. Therefore, bombesin can chaperone cytotoxic drugs straight to these tumors. A cytotoxic analog of bombesin containing doxorubicin displayed disease stabilization through phase-I clinical trials against ovarian and endometrial carcinomas.[49] It is now undergoing phase-I or phase-II clinical trials in other various malignancies.[4]
Measuring bombesin stimulated gastrin response can serve as a marker for patients who are at very high risk for gastric cancer. Patients with late-onset hypogammaglobulinemia are at very high risk for gastric cancer. Late-onset hypogammaglobulinemia patients have reduced secretion of gastrin after stimulation with bombesin. Stimulated gastrin response can, therefore, be useful as a marker for this type of immunodeficiency. Plasma gastrin responses to stimulation with bombesin correlate with late-onset hypogammaglobulinemia. (72% sensitivity , 100% specificity). Bombesin can help to distinguish late-onset hypogammaglobulinemia from X-linked agammaglobulinemia, early-onset hypogammaglobulinemia, and lymphoproliferative cancer.[50] This differentiation would also help to identify patients with an increased risk for gastric cancer. Plasma gastrin responses to stimulation with bombesin correlate with late-onset hypogammaglobulinemia.
A bombesin/gastrin-releasing peptide antagonist might hold promise as a possible new agent for the treatment of breast cancer.[51]
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