Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer

Moody, Terry W.; Nuche-Berenguer, Bernardo; Jensen, Robert T.

doi:10.1097/med.0000000000000218

Cited by 89 publications

(78 citation statements)

References 167 publications

(258 reference statements)

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“…h ). Vasoactive intestinal peptide (VIP), a major neuropeptide with prominent growth effects on neoplasms, was significantly upregulated in SR‐del/IL‐17‐dip and DR‐del/IL‐17‐dip CRC tumors and appeared to be negatively modified in IL‐17‐gain tumors (Fig. i ).…”

Section: Resultsmentioning

confidence: 99%

IL‐17R deletion predicts high‐grade colorectal cancer and poor clinical outcomes

Yan

Huang

Boudreau

et al. 2019

Intl Journal of Cancer

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The IL‐17 receptor (IL‐17R) has a perplexing role in cancer, which may be explained by its yin‐yang signaling pathways. Recently, the critical role of IL‐17R in maintaining basal levels of A20—a key negative regulator of NF‐κB and JNK‐c‐Jun pathways has been demonstrated in cancer cell lines. Cross‐cancer analyses of somatic copy number alterations in IL‐17RA, IL‐17RC and A20 genes reveal that IL‐17RA‐deletion is common in colorectal cancer (CRC) patients, representing 24, 26, 37 and 49% of stage I, II, III and IV of patients, respectively, and mutually exclusive with patients displaying microsatellite instability. Importantly, patients with IL‐17R‐deletion or concurrent deletions of A20 show significantly reduced overall survival. Analysis of multiple published microarray studies confirms that IL‐17RA expression is significantly reduced in CRC samples compared to normal counterparts, and its level is closely associated with A20 expression. Analyses of RNAseq data indicate that tumors with IL‐17R‐deletion express strong molecular markers of tumor invasion, growth and metastasis. Notably, approximately 20 genes responsible for protein synthesis and mitochondrial metabolism are inversely correlated with both IL‐17RA and A20. Immunohistochemistry staining in human colorectal tissue arrays further reveals that high‐grade tumors have significantly reduced IL‐17RA staining compared to low‐grade tumors. Thus, collective evidence strongly supports a previously unrecognized CRC‐promoting mechanism triggered by IL‐17RA‐deletion and highlights its utility as a prognostic marker in CRC.

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Section: Resultsmentioning

confidence: 99%

IL‐17R deletion predicts high‐grade colorectal cancer and poor clinical outcomes

Yan

Huang

Boudreau

et al. 2019

Intl Journal of Cancer

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“…Alternatively, somatostatin inhibits the tumor growth, and, thus, somatostatin analogue is used effectively for treatment of liver or pancreatic cancer . Overexpression of VIP receptors VPAC1 and VPAC2 is seen in many human cancers . Although, these receptors are known to be expressed in HCC, their roles in tumor growth and progression remain undetermined.…”

Section: Discussionmentioning

confidence: 99%

Vasoactive intestinal peptide increases apoptosis of hepatocellular carcinoma by inhibiting the cAMP/Bcl‐xL pathway

et al. 2018

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Vasoactive intestinal peptide (VIP) is a modulator of inflammatory responses. VIP receptors are expressed in several tumor types, such as colorectal carcinoma. The study described herein was conducted to confirm the presence of VIP and its receptors (VPAC1 and VPAC2) in surgically resected hepatocellular carcinoma (HCC) tissues and in the HCC cell line Huh7. The mechanism responsible for apoptosis of HCC cells was then examined because VIP treatment (10−10 M) significantly suppressed proliferation of Huh7 cells. In examining apoptosis‐related proteins, we found caspase‐3 to be significantly increased and Bcl‐xL and cyclic AMP (cAMP) response element‐binding protein (CREB) to be significantly decreased in Huh7 cells cultured with VIP. Furthermore, the CREB level and phosphorylation were reduced. These effects were reversed by the addition of VIP receptor antagonist or cAMP antagonist Rp‐cAMPS. Pretreatment with cAMP analogue blocked the increased apoptosis, suggesting that VIP induces apoptosis via a PKA‐independent signaling mechanism. Our data indicate that VIP prevents the progression of HCC by apoptosis through the cAMP/Bcl‐xL pathway.

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“…Notably, activating TSH receptor mutations appears to be the cause of some thyroid cancers with corresponding hyperthyroidism ( Grob et al, 2014 ; Kyrilli et al, 2017 ; Mon et al, 2018 ). Moreover, many cancers are known to overexpress receptors, which, as discussed above, can result in enhanced constitutive activity that may play a role in cancer progression and metastasis ( Li et al, 2005 ; Dorsam and Gutkind, 2007 ; Moody et al, 2016 ; Insel et al, 2018 ; Xu et al, 2018 ). It would seem to be a worthwhile effort to explore the therapeutic potential of inverse agonists in cancer treatment.…”

Section: Constitutive Activity and Inverse Agonismmentioning

confidence: 99%

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity

Berg¹,

Clarke²

2018

International Journal of Neuropsychopharmacology

121

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Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display “constitutive” activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured. Thus, a drug can be simultaneously an agonist, an antagonist, and an inverse agonist acting at the same receptor. This means that drugs have an additional level of selectivity (signaling selectivity or “functional selectivity”) beyond the traditional receptor selectivity. Both inverse agonism and functional selectivity need to be considered when drugs are used as medicines or as research tools.

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Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer

Cited by 89 publications

References 167 publications

IL‐17R deletion predicts high‐grade colorectal cancer and poor clinical outcomes

IL‐17R deletion predicts high‐grade colorectal cancer and poor clinical outcomes

Vasoactive intestinal peptide increases apoptosis of hepatocellular carcinoma by inhibiting the cAMP/Bcl‐xL pathway

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity

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