Acetylcholine signaling system in progression of lung cancers

Friedman, Jamie; Richbart, Stephen D.; Merritt, Justin C.; Brown, Kathleen C.; Nolan, Nicholas; Akers, Austin T.; Lau, Jamie K.; Robateau, Zachary R.; Miles, Sarah; Dasgupta, Piyali

doi:10.1016/j.pharmthera.2018.10.002

Cited by 86 publications

(111 citation statements)

References 374 publications

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“…The role of nAChRs has been intensely studied in the growth, angiogenesis and metastasis of lung cancer . The reason for this trend is due to GWAS studies showing genetic variations in α5‐α3‐β4 nAChR cluster (CHRNA5‐CHRNA3‐CHRNB4) associated with increased risk of death from lung cancer, COPD and tobacco‐related cancers .…”

Section: Discussionmentioning

confidence: 99%

“…ChIP assays confirmed that the CHRNA5 promoter The role of nAChRs has been intensely studied in the growth, angiogenesis and metastasis of lung cancer. 13,30 The reason for this trend is due to GWAS studies showing genetic variations in α5-α3-β4 nAChR cluster (CHRNA5-CHRNA3-CHRNB4) associated with increased risk of death from lung cancer, COPD and tobacco-related cancers. 14,31 Conventionally, the α7-nAChR is thought to mediate the proliferative, pro-angiogenic and pro-metastatic activity of nicotine in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Among different members of nicotinic receptor family, the intracellular domain of α7 nAChR is one of the most well conserved, and the role of α7‐nAChR in non‐neuronal systems has been predominantly studied . However, nAChR subunits and downstream signalling pathways vary from different types of NSCLC . Notably, genome‐wide association studies (GWAS) have showed that variants in the region encoding the α3, β4 and α5 subunits of nAChRs are significantly involved in nicotine dependence and lung carcinogenesis .…”

Section: Introductionmentioning

confidence: 99%

“…12 However, nAChR subunits and downstream signalling pathways vary from different types of NSCLC. 13 Notably, genome-wide association studies (GWAS) have showed that variants in the region encoding the α3, β4 and α5 subunits of nAChRs are significantly involved in nicotine dependence and lung carcinogenesis. 14 Especially, α5-nAChR was highly associated with lung cancer risk and nicotine dependence.…”

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confidence: 99%

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α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

Chen

Jia

Zhang

et al. 2020

J Cellular Molecular Medi

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Recent studies have showed that α5 nicotinic acetylcholine receptor (α5‐nAChR) is closely associated with nicotine‐related lung cancer. Our previous studies also demonstrated that α5‐nAChR mediates nicotine‐induced lung carcinogenesis. However, the mechanism by which α5‐nAChR functions in lung carcinogenesis remains to be elucidated. Jab1/Csn5 is a key regulatory factor in smoking‐induced lung cancer. In this study, we explored the underlying mechanisms linking the α5‐nAChR‐Jab1/Csn5 axis with lung cancer epithelial‐mesenchymal transition (EMT) and metastasis, which may provide potential therapeutic targets for future lung cancer treatments. Our results demonstrated that the expression of α5‐nAChR was correlated with the expression of Jab1/Csn5 in lung cancer tissues and lung cancer cells. α5‐nAChR expression is associated with Jab1/Csn5 expression in lung tumour xenografts in mice. In vitro, the expression of α5‐nAChR mediated Stat3 and Jab1/Csn5 expression, significantly regulating the expression of the EMT markers, N‐cadherin and Vimentin. In addition, the down‐regulation of α5‐nAChR or/and Stat3 reduced Jab1/Csn5 expression, while the silencing of α5‐nAChR or Jab1/Csn5 inhibited the migration and invasion of NSCLC cells. Mechanistically, α5‐nAChR contributes to EMT and metastasis by regulating Stat3‐Jab1/Csn5 signalling in NSCLC, suggesting that α5‐nAChR may be a potential target in NSCLC diagnosis and immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

Chen

Jia

Zhang

et al. 2020

J Cellular Molecular Medi

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“…Acetylcholine is known to be secreted by lung cancer cells into the extracellular environment, stimulating growth of cancerous cells in lung tumors 65,66 . It acts as an autocrine growth factor for human lung cancer 67 by binding to nicotinic and muscarinic receptors on lung cancer cells, accelerating their proliferation, migration, and invasion 67 . Acetylcholine was found to have mitogenic effects in A549 and in p53-negative human lung carcinoma NSCLC H1299 cells, increasing the expression of matrix metalloproteinases and downregulating the expression of E-cadherin in A549 human NSCLC 61,67 .…”

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confidence: 99%

IGFBP-3 Blocks Hyaluronan-CD44 Signaling, Leading to Increased Acetylcholinesterase Levels in A549 Cell Media and Apoptosis in a p53-Dependent Manner

Price

Muterspaugh

Clegg

et al. 2020

Sci Rep

105

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Insulin-like growth factor binding protein-3 (IGFBP-3) belongs to a family of six IGF binding proteins. We previously found that IGFBP-3 exerts its cytotoxic effects on A549 (p53 wild-type) cell survival through a mechanism that depends on hyaluronan-CD44 interactions. To shed light on the mechanism employed, we used CD44-negative normal human lung cells (HFL1), A549, and H1299 (p53-null) lung cancer cells. A synthetic IGFBP-3 peptide ( 215 -KKGfYKKKQcRpSKGRKR-232 ) but not the mutant (K228AR230A), was able to bind hyaluronan more efficiently than the analogous sequences from the other IGFBPs. In a manner comparable to that of the IGFBP-3 protein, the peptide blocked hyaluronan-CD44 signaling, and more effectively inhibited viability of A549 cells than viability of either H1299 or HFL1 cell lines. Treatment with the IGFBP-3 protein or its peptide resulted in increased acetylcholinesterase concentration and activity in the A549 cell media but not in the media of either HFL1 or H1299, an effect that correlated with increased apoptosis and decreased cell viability. These effects were diminished upon the same treatment of A549 cells transfected with either p53 siRNA or acetylcholinesterase siRNA. Taken together, our results show that IGFBP-3 or its peptide blocks hyaluronan-CD44 signaling via a mechanism that depends on both p53 and acetylcholinesterase.Lung cancer is a devastating human disease and among the most common causes of cancer deaths worldwide 1,2 . Of all cases of the disease, non-small cell lung cancer (NSCLC) accounts for approximately 85% 3 .CD44 is a type 1 transmembrane cell-surface glycoprotein with tumor promoting functions in many types of cancer cells 4-7 . It is the main cell surface receptor for hyaluronan (HA) 5-9 . Found on the extracellular side of the cell membrane is the CD44 globular HA-binding domain (HABD) 9,10 shown previously to bind HA as a globular water-soluble protein 11 . CD44 is encoded by a single gene 5,6,12 and many different variant isoforms (CD44v) are generated by alternative splicing that yield different patterns of amino acid insertion into the stalk domain of CD44 with the smallest being the standard CD44 (CD44s) 5,13-15 . Residues 32-123 in the N-terminal domain of CD44, common to both CD44s and CD44v isoforms, contain the HA-binding motif 16 . Assessment of CD44 expression in human lung cancer cell lines 17 , including A549 and H1299 used in this study, showed that the predominant isoform expressed is CD44s 18 . Being a common marker for tumor-initiating cells/cancer stem cells in human carcinomas, CD44 has gained much attention in the cancer literature 14 . HA-CD44 binding is known to modulate numerous downstream signaling cascades, such as the ERK1/2/MAPK and PI3K/Akt pathways, leading to tumor cell proliferation, survival, chemoresistance, and invasiveness 5,7,12,19 .HA is a non-sulfated, anionic glycosaminoglycan 5,16,20,21 polymer composed of the disaccharide sequence (D-glucuronic acid and D-N-acetylglucosamine) without known post-synthetic modification 6,22-24 ...

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The Role of Nerve Fibers in the Tumor Immune Microenvironment of Solid Tumors

2022

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The concept of solid tumors innervation and tumor associated nerves is a recently emerging area of cancer research, with several studies showing strong evidence of its critical role in tumor biology. [3] Numerous studies in the field of cancer research and neuroscience have identified nerves as key promoters of different pathways of tumor growth and dissemination. In addition, it has been shown that nerves play immune regulatory functions and constitute an essential component of cellular microenvironments. [4] Furthermore, nerves seem to modulate many signaling pathways in tumor cells and other cellular elements of the TME. [5] The assessment of the presence, type, and density of nerve fibers performed in tumor tissue offers several opportunities to study nerve-related mechanisms implicated in tumor development. This is supported by studies revealing that differences of nerve fiber density in tumors, such as in pancreatic carcinoma, correlated patient's prognosis. [6] There are many techniques that can be used to evaluate nerve fibers in tissue, namely, routine hematoxylin and eosin (H&E) staining combined with micro scopy evaluation and more advanced technologies including artificial intelligence or hi-plex techniques that allow the analysis of several biomarkers in limited tissue samples. [7,8] More importantly, understanding the mutual interactions between nerves and solid tumors may accelerate the development of novel drugs and surgical therapeutic approaches. [9] Nerves seem to have a trophic and immune impact in tumors similarly to the well-known nerve functions in tissue regeneration, and in immunity, these features can potentially be exploited to develop novel and more efficacious therapeutic approaches. [10,11] These new therapeutic targets, alone or in combination with chemotherapy or immunotherapy could slow or stop cancer progression. [12] In this review we will briefly describe the historical background of the study of nerves in tumors, the mechanisms associated with this emergent concept of nerve fibers as important players in the TME including innervation of solid tumors, mechanisms of nerve fiber neogenesis, the complex interactions among nerve fibers and TME elements including immune cells, and its impact in tumor initiation and disease progression; we will also provide a summary of the approaches that can be used to assess tumor associated nerves in tissue;The importance of neurons and nerve fibers in the tumor microenvironment (TME) of solid tumors is now acknowledged after being unexplored for a long time; this is possible due to the development of new technologies that allow in situ characterization of the TME. Recent studies have shown that the density and types of nerves that innervate tumors can predict a patient's clinical outcome and drive several processes of tumor biology. Nowadays, several efforts in cancer research and neuroscience are taking place to elucidate the mechanisms that drive tumor-associated innervation and nerve-tumor and nerve-immune interaction. Assessment of neurons a...

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Acetylcholine signaling system in progression of lung cancers

Cited by 86 publications

References 374 publications

α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

IGFBP-3 Blocks Hyaluronan-CD44 Signaling, Leading to Increased Acetylcholinesterase Levels in A549 Cell Media and Apoptosis in a p53-Dependent Manner

The Role of Nerve Fibers in the Tumor Immune Microenvironment of Solid Tumors

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