TMEM16A Ca2+-activated Cl− channel inhibition ameliorates acute pancreatitis via the IP3R/Ca2+/NFκB/IL-6 signaling pathway

Wang, Qinghua; Bai, Lichuan; Luo, Shuya; Wang, Tianyu; Yang, Fan; Xia, Jialin; Wang, Hui; Ma, Ke; Liu, Mei; Wu, S. C.; Wang, Huijie; Guo, Shi‐Bin; Sun, Xiaohong; Xiao, Qinghuan

doi:10.1016/j.jare.2020.01.006

Cited by 44 publications

(57 citation statements)

References 40 publications

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“…4i, j). Thus, Ca 2+ release and SOCE are coupled and are augmented by deletion of Pkd1, probably due to upregulation of TMEM16A 23,[25][26][27] . SOCE is potently blocked by the inhibitors of Orai channels and transient receptor potential (Trp) channels, YM58483 and SK&F96365, respectively, suggesting a contribution of both channels to enhanced SOCE in Pkd1 −/− cells ( Fig.…”

Section: Knockdown Of Pkd1 Causes Upregulation Of Tubular Expressionmentioning

confidence: 99%

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

et al. 2020

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In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl − secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca 2+ signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca 2+ signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmem16a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.

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Section: Knockdown Of Pkd1 Causes Upregulation Of Tubular Expressionmentioning

confidence: 99%

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

et al. 2020

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“…The signal transducer and activator of transcription (STAT) transcription factors were shown to control ANO1 gene transcription in several studies. STAT3 is important for ANO1 transcription in response to IL-6 in pancreatic acinar cells (Wang et al, 2020) and in response to EGF in breast cancer cells (Wang et al, 2019). EGF-induced ANO1 expression in colonic epithelial cancer cells was also dependent on the activity of protein kinase C-δ (PKCδ) and phosphatidylinositol 3-kinase (PI3K), but the link to STAT3 was not investigated (Mroz and Keely, 2012).…”

Section: Regulation Of Ano1 Expressionmentioning

confidence: 99%

“…This review summarizes the current knowledge of mechanisms governing the regulation of ANO1 expression and ANO1-induced intracellular signaling. (Table 1) Most notably, ANO1 expression is increased in response to several interleukins including IL-4 in bronchial epithelial cells (Caputo et al, 2008;Caci et al, 2015) and human nasal epithelial cells (Kang et al, 2017), IL-6 in pancreatic acinar cells (Wang et al, 2020), and IL-13 in human bronchial epithelial cells (Lin et al, 2015;Qin et al, 2016), human nasal polyp epithelial cells and human esophageal keratinocytes (Vanoni et al, 2020). Epidermal growth factor (EGF) promotes ANO1 expression in colonic epithelial cancer cells (Mroz and Keely, 2012) and in breast cancer cells (Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…There are other mechanisms by which ANO1 activation facilitates an increase in the intracellular Ca 2+ concentration. ANO1 co-immunoprecipitated with the inositol 1,4,5-trisphosphate receptor (IP3R), was activated by IP3R-mediated Ca 2+ release, but also contributed to Ca 2+ release induced by cholecystokinin analog, cerulain, in pancreatic acinar AR42J cells ( Wang et al, 2020 ). ANO1 is also required for EGF-induced store-operated calcium entry (SOCE) in pancreatic cancer cells ( Crottes et al, 2019 ); however, in both latter studies, the precise mechanism by which ANO controls Ca 2+ signaling was not determined.…”

Section: Introductionmentioning

confidence: 99%

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Calcium-Activated Chloride Channel ANO1/TMEM16A: Regulation of Expression and Signaling

Dulin

2020

Front. Physiol.

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Anoctamin-1 (ANO1), also known as TMEM16A, is the most studied member of anoctamin family of calcium-activated chloride channels with diverse cellular functions. ANO1 controls multiple cell functions including cell proliferation, survival, migration, contraction, secretion, and neuronal excitation. This review summarizes the current knowledge of the cellular mechanisms governing the regulation of ANO1 expression and of ANO1-mediated intracellular signaling. This includes the stimuli and mechanisms controlling ANO1 expression, agonists and processes that activate ANO1, and signal transduction mediated by ANO1. The major conclusion is that this field is poorly understood, remains highly controversial, and requires extensive and rigorous further investigation.

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“…Besides, IL-6 was always considered to participate in acute pancreatitis by facilitating neutrophils infiltration. Latest research provided novel cellular signal pathway that IL-6 promoted TMEM16A expression via activating IL-6R/STAT3 signal to facilitate pathogenesis of acute pancreatitis (Wang et al., 2020 ).…”

Section: Molecular and Cellular Mechanisms Of Acute Pancreatitismentioning

confidence: 99%

Drug discovery and formulation development for acute pancreatitis

et al. 2020

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Acute pancreatitis is a sudden inflammation and only last for a short time, but might lead to a life-threatening emergency. Traditional drug therapy is an essential supportive method for acute pancreatitis treatment, yet, failed to achieve satisfactory therapeutic outcomes. To date, it is still challenging to develop therapeutic medicine to redress the intricate microenvironment promptly in the inflamed pancreas, and more importantly, avoid multi-organ failure. The understanding of the acute pancreatitis, including the causes, mechanism, and severity judgment, could help the scientists bring up more effective intervention and treatment strategies. New formulation approaches have been investigated to precisely deliver therapeutics to inflammatory lesions in the pancreas, and some even could directly attenuate the pancreatic damages. In this review, we will briefly introduce the involved pathogenesis and underlying mechanisms of acute pancreatitis, as well as the traditional Chinese medicine and the new drug option. Most of all, we will summarize the drug delivery strategies to reduce inflammation and potentially prevent the further development of pancreatitis, with an emphasis on the bifunctional nanoparticles that act as both drug delivery carriers and therapeutics.

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TMEM16A Ca2+-activated Cl− channel inhibition ameliorates acute pancreatitis via the IP3R/Ca2+/NFκB/IL-6 signaling pathway

Cited by 44 publications

References 40 publications

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

Calcium-Activated Chloride Channel ANO1/TMEM16A: Regulation of Expression and Signaling

Drug discovery and formulation development for acute pancreatitis

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