Small Molecule-facilitated Degradation of ANO1 Protein

Bill, Anke; Hall, Michelle Lynn; Borawski, Jason; Hodgson, Catherine; Jenkins, Jeremy L.; Piéchon, Philippe; Popa, M. Oana; Rothwell, Christopher; Tranter, Pamela; Tria, Scott; Wagner, Trixie; Whitehead, Lewis; Gaither, L. Alex

doi:10.1074/jbc.m114.549188

Cited by 73 publications

(57 citation statements)

References 43 publications

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“…Previous studies have shown that pharmacological inhibition of ANO1 by small-molecule ANO1 inhibitors such as T16A inh -A01, CaCC inh -A01, tannic acid, MONNA and idebenone significantly decreased cell proliferation, migration or invasion abilities in human cancer cell lines expressing ANO1, even though the pathophysiological roles of ANO1 in cancer and the underlying molecular mechanisms of anticancer effect of downregulation of ANO1 are not clearly understood [12, 13, 23, 24]. Interestingly, as shown in Fig 5A and 5C, luteolin inhibited cell proliferation and migration of PC-3 human prostate cancer cells expressing high levels of ANO1 much more potently than that of ANO1-deficient PC-3 cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ANO1 by luteolin and its cytotoxicity in human prostate cancer PC-3 cells

et al. 2017

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Anoctamin 1 (ANO1), a calcium-activated chloride channel, is highly amplified in prostate cancer, the most common form of cancer and leading causes of cancer death in men, and downregulation of ANO1 expression or its functional activity is known to inhibit cell proliferation, migration and invasion in prostate cancer cells. Here, we performed a cell-based screening for the identification of ANO1 inhibitors as potential anticancer therapeutic agents for prostate cancer. Screening of ~300 selected bioactive natural products revealed that luteolin is a novel potent inhibitor of ANO1. Electrophysiological studies indicated that luteolin potently inhibited ANO1 chloride channel activity in a dose-dependent manner with an IC50 value of 9.8 μM and luteolin did not alter intracellular calcium signaling in PC-3 prostate cancer cells. Luteolin inhibited cell proliferation and migration of PC-3 cells expressing high levels of ANO1 more potently than that of ANO1-deficient PC-3 cells. Notably, luteolin not only inhibited ANO1 channel activity, but also strongly decreased protein expression levels of ANO1. Our results suggest that downregulation of ANO1 by luteolin is a potential mechanism for the anticancer effect of luteolin.

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Section: Discussionmentioning

confidence: 99%

Inhibition of ANO1 by luteolin and its cytotoxicity in human prostate cancer PC-3 cells

et al. 2017

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“…FaDu cells were engineered to express control scrambled shRNA or TMEM16A-targeting shRNA in doxycycline-inducible manner as previously described by Britschgi, Bill et al [14, 15]. These cells were cultured in DMEM containing 10% tetracycline-free serum.…”

Section: Methodsmentioning

confidence: 99%

TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression

Godse

Khan

Yochum

et al. 2017

Clinical Cancer Research

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Purpose TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCC), raising the possibility of an anti-apoptotic role in malignant cells. The present study investigated this using a multi-modal, translational investigation. Experimental Design Combination of 1) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression 2) in vivo studies assessing similar outcomes, and 3) molecular and staining analysis of human HNSCC samples. Results TMEM16A expression was found to correlate with greater tumor size, increased Erk 1/2 activity, less Bim expression, and less apoptotic activity overall in human HNSCC. These findings were corroborated in subsequent in vitro and in vivo studies and expanded to include a cisplatin-resistant phenotype with TMEM16A overexpression. A cohort of 41 patients with laryngeal cancer demonstrated that cases that recurred after chemoradiation failure were associated with a greater TMEM16A overexpression rate than HNSCC that did not recur. Conclusions Ultimately, this study implicates TMEM16A as a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease.

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“…36 The non-selective CaCC inhibitor 1 was shown to accelerate the degradation of TMEM16A in cancer cells by the ubiquitin-proteasome pathway by a mechanism that may not involve channel inhibition. 37 Several recent studies address inhibitor selectivity. Studies of 1 , 2 , and 3 in isolated resistance arteries suggested poor TMEM16A selectivity for all three compounds.…”

Section: Introductionmentioning

confidence: 99%

Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)

et al. 2017

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Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report by screening the discovery of 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A, and analysis of 48 synthesized analogs (10ab–10bw) of the original AACT compound (10aa). Structure-activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 ~ 30 nM, ~3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.

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Small Molecule-facilitated Degradation of ANO1 Protein

Cited by 73 publications

References 43 publications

Inhibition of ANO1 by luteolin and its cytotoxicity in human prostate cancer PC-3 cells

Inhibition of ANO1 by luteolin and its cytotoxicity in human prostate cancer PC-3 cells

TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression

Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)

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