CARCINOGENESIS
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2024
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IF 3.3
Yang Xin,Cui Limei,Liu Zhonglu,Li Yumei,Wu Xinxin,Tian Ruxian,Jia Chuanliang,Ren Chao,Mou Yakui,Song Xicheng
Previous studies have indicated that transmembrane protein 16A (TMEM16A) plays a crucial role in the pathogenesis and progression of various tumors by influencing multiple signaling pathways. However, the role of TMEM16A in regulating autophagy via the mammalian target of rapamycin (mTOR) pathway and its impact on the development of hypopharyngeal squamous cell carcinoma (HSCC) remain unclear. Immunohistochemistry and western blotting were used to assess the expression of TMEM16A in HSCC tissues and metastatic lymph nodes. Manipulation of TMEM16A expression levels was achieved in the FaDu cell line through overexpression or knockdown, followed by assessment of its biological effects using cell colony formation, wound healing, transwell, and invasion assays. Additionally, apoptosis and autophagy-related proteins, as well as autophagosome formation, were evaluated through western blotting, transmission electron microscopy, and immunofluorescence following TMEM16A knockdown or overexpression in FaDu cells. Our study revealed significantly elevated levels of TMEM16A in both HSCC tissues and metastatic lymph nodes compared to normal tissues. In vitro experiments demonstrated that silencing TMEM16A led to a notable suppression of HSCC cell proliferation, invasion, and migration. Furthermore, TMEM16A silencing effectively inhibited tumor growth in xenografted mice. Subsequent investigations indicated that knockdown of TMEM16A in HSCC cells could suppress mTOR activation, thereby triggering autophagic cell death by upregulating sequestosome-1 (SQSTM1/P62) and microtubule-associated protein light chain 3 II (LC3II). This study highlights the crucial role of TMEM16A in modulating autophagy in HSCC, suggesting its potential as a therapeutic target for the treatment of this malignancy.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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病理学
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PubMed
高影响因子
JOURNAL OF MEMBRANE BIOLOGY
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2017
·Vol. 250
·期 5
·483-492
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IF 1.696
Chai Ran,Chen Yafei,Yuan Hongbo,Wang Xuzhao,Guo Shuai,Qi Jinlong,Zhang Hailin,Zhan Yong,An Hailong
Calcium-activated chloride channels (CaCCs) play vital roles in a variety of physiological processes. Dysfunction of the CaCCs is implicated in many diseases. Drug discovery targeting at CaCCs has recently become possible with the determination that TMEM16A is the molecular identity of CaCCs. In this study, we demonstrated that resveratrol (RES), a Chinese traditional medicine compound, is a novel activator of TMEM16A. The yellow fluorescence protein quenching assay and measurement of intracellular calcium fluorescence intensity show that RES activates TMEM16A channels in an intracellular Ca 2+ -independent way. The data of inside-out patch clamp revealed that RES dose-dependently activates TMEM16A (EC 50 = 47.92 ± 9.35 μM). Furthermore, RES enhanced the contractions of the ileum of guinea pigs by activating the TMEM16A channel, which indicated that RES might be a promising drug for the treatment of gastrointestinal hypomotility. As RES was able to induce TMEM16A channel activation, TMEM16A can be added to the list of RES drug targets.
研究领域:
药理学
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生理学
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药物发现
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Zhichen Wang,Ruili Geng,Yanai Chen,Jianglei Qin,Shuai Guo
The incidence and mortality rates of lung cancer have remained high for several decades, necessitating the discovery of new drugs and the development of effective treatment strategies. This study identified matairesinoside (MTS) as a potent inhibitor of TMEM16A, a novel drug target for lung cancer. Molecular simulation combined with site-directed mutagenesis experiments confirmed the key binding sites of MTS and TMEM16A. Cell experiments demonstrated that MTS significantly inhibited the growth, migration, and invasion of lung cancer cells, while inducing apoptosis. Gene knockdown and overexpression studies further revealed that TMEM16A is the target for MTS in regulating lung cancer cell growth. Western blot analysis elucidated the signaling transduction network involved in MTS-mediated regulation of lung cancer. Building upon these findings, a biodegradable self-healing functional hydrogel was developed to load MTS, aiming to enhance therapeutic efficacy and minimize side effects in vivo . Animal experiments demonstrated that the hydrogel/MTS formulation exhibited satisfactory inhibitory effects on lung cancer and mitigated the side effects associated with direct MTS injection. This study identified MTS as a potential candidate for anti-lung cancer therapy with well-defined pharmacological mechanisms. Moreover, the targeted drug delivery system utilizing the hydrogel/MTS platform offers a promising approach for lung cancer treatment.
研究领域:
肿瘤学
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药理学
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分子生物学
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生物医学工程
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2020
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IF 4.96
Shuai Guo,Liang Qiu,Yafei Chen,Xuzhao Wang,Biao Ma,Chang Qu,Jianmin Cui,Hailin Zhang,Chengfen Xing,Yong Zhan,Hailong An
To overcome the adverse effects of conventional chemotherapy for cancers, various nanoparticles based drug delivery systems have been developed. However, nanoparticles delivering drugs directly to kill tumor cells still faced with challenges, because tumors possessed adopt complex mechanism to resist damages, which compromised the therapeutic efficacy. TMEM16A/CaCCs (Calcium activates chloride channels) has been identified to be overexpressed in lung adenocarcinoma which can serve as a novel tumor specific drug target in our previous work. Here, we developed a novel dual-targeted antitumor strategy via designing a novel nano-assembled, pH-sensitive drug-delivery system loading with specific inhibitors of TMEM16A against lung adenocarcinoma. For validation, we assayed the novel dual-targeting therapy on xenograft mouse model which exhibited significant antitumor activity and not affect mouse body weight. The dual targeting therapy accomplished in this study will shed light on the development of advanced antitumor strategy.
研究领域:
肿瘤学
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药学
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纳米技术
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分子生物学
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2021
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IF 6.53
Pengmei Guo,Yu Liu,Xiaojia Xu,Guijin Ma,Xiaomin Hou,Yanying Fan,Mingsheng Zhang
Background Severe acidosis deteriorates cardiac injury. Rat coronary arteries (RCAs) are unusually hypercontractive to extracellular (o) acidosis (EA). TMEM16A-encoded anoctamin 1 (ANO1), a Ca 2+ -activated chloride channel (CaCC), plays an important role in regulating coronary arterial tension. Purpose We tested the possibility that the activation of CaCCs in the arterial smooth muscle cell (ASMC) contributes to EA-induced RCA constriction. Methods ANO1 expression was detected with immunofluorescence staining and Western blot. TMEM16A mRNA was assessed with quantitative Real-Time PCR. Cl - currents and membrane potentials were quantified with a patch clamp. The vascular tension was recorded with a myograph. Intracellular (i) level of Cl - and Ca 2+ was measured with fluorescent molecular probes. Results ANO1 was expressed in all tested arterial myocytes, but was much more abundant in RCA ASMCs as compared with ASMCs isolated from rat cerebral basilar, intrarenal and mesenteric arteries. EA reduced [Cl - ] i levels, augmented CaCC currents exclusively in RCA ASMCs and depolarized RCA ASMCs to a greater extent. Cl - deprivation, which depleted [Cl - ] i by incubating the arteries or their ASMCs in Cl - -free bath solution, decreased EA-induced [Cl - ] i reduction, diminished EA-induced CaCC augmentation and time-dependently depressed EA-induced RCA constriction. Inhibitor studies showed that these EA-induced effects including RCA constriction, CaCC current augmentation, [Cl - ] i reduction and/or [Ca 2+ ] i elevation were depressed by various Cl - channel blockers, [Ca 2+ ] i release inhibitors and L -type voltage-gated Ca 2+ channel inhibitor nifedipine. ANO1 antibody attenuated all observed changes induced by EA in RCA ASMCs. Conclusion The greater activity of RCA ASMC CaCCs complicated with an enhanced Ca 2+ mobilization from both [Ca 2+ ] i release and [Ca 2+ ] o influx plays a pivotal role in the distinctive hypercontractility of RCAs to acidosis. Translation of these findings to human beings may lead to a new conception in our understanding and treating cardiac complications in severe acidosis.
研究领域:
心血管生理学
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分子生物学
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药理学
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PubMed
高影响因子
DIGESTIVE DISEASES AND SCIENCES
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2018
·Vol. 63
·期 12
·3329-3338
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IF 2.819
Lin Meng-juan,Yu Bao-ping
Background Irritable bowel syndrome (IBS) is a common disease with intestinal dysmotility, whose mechanism remains elusive. TMEM16A is a calcium-activated chloride channel (CaCC) involved in intestinal slow-wave generation. Aims To investigate whether TMEM16A is involved in colonic dysmotility in IBS. Methods A rat model of IBS was established by chronic water avoidance stress (WAS). Colonic pathological alterations were evaluated histologically, and intestinal motility was assessed by intestinal transit time (ITT) and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response (VMR) to colorectal distension (CRD). TMEM16A expression was evaluated by RT-PCR, Western blot, and immunofluorescence. Colonic muscle strip contractility was measured by isometric transducers, and the effect of niflumic acid (NFA), a CaCC antagonist, on colonic motility was examined. Results After 10 days of WAS exposure, ITT was decreased and FWC was elevated. Furthermore, VMR magnitude of WAS rats in response to CRD was significantly enhanced. Protein and mRNA levels of TMEM16A in colon were considerably increased after WAS. The percentage of TMEM16A-positive neurons in myenteric plexus (MP) of WAS rats was significantly higher than controls. Pharmacological blockade of TMEM16A activity by NFA considerably enhanced ITT, with concentration-dependent declines in FWC and VMR magnitude in NFA-treated rats. Further, spontaneous contraction of colonic strips of NFA-treated rats was significantly ameliorated in a concentration-dependent manner in vitro. Conclusions Upregulation of TMEM16A in MP neurons may play an important role in chronic stress-induced colonic hypermotility, making CaCC-blocking drugs a putatively effective treatment method for colonic hypermotility in IBS.
研究领域:
胃肠病学
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神经胃肠病学
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药理学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2024
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IF 6.7
Xue Bai,Yinuo Liu,Yuchen Cao,Zhouye Ma,Yue Chen,Shuai Guo
Background Lung cancer is a highly malignant disease with limited treatment options and significant adverse effects . It is urgent to develop novel treatment strategies for lung cancer. In recent years, TMEM16A has been confirmed as a specific drug target for lung cancer. The development of TMEM16A-targeting drugs and combined administration for the treatment of lung cancer has become a research hotspot. Methods Fluorescence screening and electrophysiological experiments were conducted to confirm the inhibitory effect of CCA on TMEM16A. Molecular dynamics simulation and site-directed mutagenesis were employed to analyze the binding mode of CCA and TMEM16A. CCK-8, colony formation, wound healing , transwell, and annexin-V experiments were conducted to explore the regulatory effects and mechanisms of CCA on the proliferation, migration, and apoptosis of lung cancer cells. Tumor model mice and pharmacokinetic experiments were used to examine the efficacy and safety of CCA and cisplatin in vivo . Results This study firstly confirmed that CCA effectively inhibits TMEM16A to exert anticancer effects and analyzed the pharmacological mechanism. CCA bound to S517/N546/E623/E633/Q637 of TMEM16A through hydrogen bonding and electrostatic interactions. It inhibited the proliferation and migration, and induced apoptosis of lung cancer cells by targeting TMEM16A. In addition, the combined administration of CCA and cisplatin exhibited a synergistic effect, enhancing the efficacy of lung cancer treatment while reducing side effects . Conclusion CCA is an effective novel inhibitor of TMEM16A, and it synergizes with cisplatin in anticancer treatment. These findings will provide new research ideas and lead compound for the combination therapy of lung cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Jiaao Shen,Zijia Man,Weiwei Li,Mengqi Guo,Zefeng Xiang,Long Ma,Xianjiang Kang,Shuai Guo
Background The incidence and mortality rates of lung cancer have consistently ranked highest among all cancers for an extended period. Identifying specific targets and developing effective drugs is crucial. In this study, we discovered that the natural compound sophoricoside, derived from Sophora japonica, targets the TMEM16A ion channel for lung cancer treatment. Methods Whole-cell patch clamp experiments were conducted to evaluate the inhibitory efficacy of sophoricoside on TMEM16A. Molecular dynamics simulations were performed to predict the affinity and the gating-related conformational changes of sophoricoside within TMEM16A. Cell proliferation, migration, and apoptosis experiments were employed to detect the regulation of sophoricoside on lung cancer cell growth. Western blot analyses were carried out to investigate the signaling mechanisms underlying the regulation of lung cancer growth by sophoricoside. In vivo xenograft tumor models were utilized to evaluate the anticancer efficacy and biosafety profile of sophoricoside. Results Sophoricoside inhibited the TMEM16A whole-cell current in a concentration-dependent manner, with an IC 50 of 14.8 ± 1.2 μM. Molecular dynamics simulations confirmed that sophoricoside bond to the extracellular vestibular region of TMEM16A, blocking chloride ion transport by inducing constriction of the hydrophobic pore regions. Subsequently, we investigated the regulatory effects of varying concentrations of sophoricoside on the growth of LA795 cells. Knocking down TMEM16A in LA795 cells and overexpressing TMEM16A in 16HBE cells established that TMEM16A was a critical target of sophoricoside. Western blot experiments demonstrated that sophoricoside inhibited the growth of LA795 cells via the several signal transduction pathways. In vivo results revealed that sophoricoside exhibits both potent anticancer effects and satisfactory biosafety. Conclusion This study identifies the natural product sophoricoside as a potential agent targeting TMEM16A to inhibit lung cancer growth, presenting a promising candidate for lung cancer treatment drugs.
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高影响因子
Materials Today Bio
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2025
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IF 10.2
Gen Li,Chunxiu Cai,Ning Zhang,Zijia Wang,Mingzhe Zhang,Quan Liu,Siyu Chen,Yanfei Shang,Chengqing Zhao,Shenzhen Ren,Hailong An
The calcium-activated chloride channel TMEM16A is frequently overexpressed in breast cancer, establishing a reciprocal activation loop with EGFR signaling pathways that play a crucial role in the proliferation of breast cancer. Consequently, the simultaneous targeting of TMEM16A and EGFR may be a promising, yet underexplored, therapeutic strategy for breast cancer. Herein, we developed a carrier-free polyphenol nanonetwork (PFGH) using procyanidin (PC), a natural polyphenolic TMEM16A inhibitor, via coordination with Fe 3+ , for co-delivering PC and gefitinib (Gef), an EGFR inhibitor. The resulting nanosystem, eliminating the requirement for additional nanocarriers, exhibited remarkable photothermal properties, pH-responsive drug release, and CD44-mediated tumor targeting. Functional assays confirmed that PFGH, under NIR irradiation, potently inhibited TMEM16A channel currents and exhibited superior antiproliferative effects compared to free PC, Gef, or their combination. RNA sequencing analysis confirmed the transcriptomic alterations in apoptosis, cell proliferation, and cancer-related pathways induced by the PFGH. In vivo studies further demonstrated that PFGH augments tumor-targeted combinatorial therapy, leveraging its photothermal properties, targeted co-delivery, and loop-suppressing activity. For the first time, our work presents a carrier-free polyphenol nanonetwork specifically engineered to co-target the TMEM16A-EGFR mutual activation loop, offering a novel, synergistic therapeutic approach for breast cancer.
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Yanan Zhang,Shaoya Rong,Shude Pang,Xiujun Fu,Yunxian Wang,Xuelu Ding,Shuai Liang,Ruihong Guo,Hui Dong
Vascular endothelial dysfunction drives sepsis progression and multi-organ failure. Although TRPA1 and TMEM16A are expressed in the vasculature, their roles in arteriolar vasorelaxation remain unclear. The vasorelaxant effects of TRPA1 and TMEM16A on the second-order branch of mesenteric resistance arteries were investigated in healthy and septic mice using a Mulvany-style wire myograph. Fluorescent Ca 2+ assays were employed to assess cytosolic Ca 2+ ([Ca 2+ ] i ) in vascular endothelial cells (VECs). A mouse sepsis model was constructed through the method of cecal ligation and puncture (CLP). Both TRPA1 and TMEM16A activation induced endothelium-dependent hyperpolarization (EDH)-mediated relaxation via functional coupling: TRPA1 triggered Ca 2+ influx and Ca 2+ -induced Ca 2+ release, amplifying TMEM16A activity. In sepsis, while ACh/EDH responses were impaired, TRPA1/TMEM16A-mediated relaxation remained intact. Channel activation improved septic mouse survival and restored ACh responses, with plasma and assay agonist concentrations in comparable ranges. This study not only elucidates the protective role of endothelial TRPA1 and TMEM16A channels against sepsis-induced vascular inflammation but also provides potential new targets for sepsis therapy.
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高影响因子
ACS Applied Materials & Interfaces
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2022
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IF 10.383
Chaoqun Li,Sai Shi,Dong Gao,Boying Li,Guoqiang Song,Yafei Chen,Hailong An,Chengfen Xing
The gated state of anion channels is involved in the regulation of proliferation and migration of tumors. Specific regulators are urgently needed for efficacious cancer ablation. For this purpose, it is essential to understand the molecular mechanisms of interaction between the regulators and anion channels and apply this knowledge to regulate anion channels. Transmembrane 16A (TMEM16A) is the molecular basis of the calcium-activated chloride channels. It is an anion channel activated by Ca2+, and the inhibition of TMEM16A is associated with a decrease in tumorigenesis. Herein, we characterized a natural compound procyanidin (PC) as an efficacious and selective inhibitor of TMEM16A with an IC50 of 10.6 ± 0.6 μM. Our research revealed the precise sites (D383, R535, and E624) of electrostatic interactions between PC and TMEM16A. Near-infrared (NIR)-light-responsive photothermal conjugated polymer nanoparticles encapsulating PC (CPNs-PC) were established to remotely target and regulate the TMEM16A anion channel. Upon NIR irradiation, CPNs-PC downregulated the signaling pathway downstream of TMEM16A and arrested the cell cycle progression of cancer cells and improved the bioavailability of PC. The tumor inhibition ratio of CPNs-PC was superior to PC by 13.4%. Our findings enabled the development of a strategy to accurately and remotely regulate anion channels to promote tumor regression using NIR-light-responsive conjugated polymer nanoparticles containing specific inhibitors of TMEM16A.
研究领域:
癌症生物学
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药学
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纳米技术
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生物医学工程
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DOI
PubMed
高影响因子
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