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Inhibition of ANO1/TMEM16A induces apoptosis in human prostate carcinoma cells by activating TNF-? signaling.

ABSTRACT: Overexpression of the Ca2+-activated chloride channel ANO1/TMEM16A is implicated in tumorigenesis, and inhibition of ANO1 overexpression suppresses xenograft tumor growth and invasiveness. However, the underlying molecular mechanism for ANO1 inhibition in suppression of tumorigenesis remains unknown. Here, we show that silencing or inhibition of endogenous ANO1 inhibits cell growth, induces apoptosis and upregulates TNF-? expression in prostate cancer PC-3 cells. Enhancement of TNF-? signaling by ANO1 knockdown leads to upregulation of phosphorylated Fas-associated protein with death domain and caspase activation. Furthermore, silencing of ANO1 inhibits growth of PC-3 xenograft tumors in nude mice and induces apoptosis in tumors via upregulation of TNF-? signaling. Taken together, our findings provide mechanistic insight into promoting apoptosis in prostate cancer cells by ANO1 inhibition through upregulation of TNF-? signaling.

SUBMITTER: Song Y

PROVIDER: S-EPMC5999606 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Inhibition of ANO1/TMEM16A induces apoptosis in human prostate carcinoma cells by activating TNF-α signaling.

Song Yan Y Gao Jian J Guan Lizhao L Chen Xiaoling X Gao Jianjun J Wang KeWei K

Cell death & disease 20180613 6

Overexpression of the Ca<sup>2+</sup>-activated chloride channel ANO1/TMEM16A is implicated in tumorigenesis, and inhibition of ANO1 overexpression suppresses xenograft tumor growth and invasiveness. However, the underlying molecular mechanism for ANO1 inhibition in suppression of tumorigenesis remains unknown. Here, we show that silencing or inhibition of endogenous ANO1 inhibits cell growth, induces apoptosis and upregulates TNF-α expression in prostate cancer PC-3 cells. Enhancement of TNF-α ...[more]

PMID: 29899325

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Project description:BackgroundIntestinal ischemia is a common clinical critical illness. Intestinal ischemia-reperfusion (IIR) leads to acute lung injury (ALI), but the causative factors of ALI are unknown. The aim of this study was to reveal the causative factors and mechanisms of IIR-induced lung injury.MethodsA mouse model of IIR was developed using C57BL/6 mice, followed by detection of lung injury status and plasma levels of inflammatory factors in sham-operated mice and model mice. Some model mice were treated with a tumor necrosis factor-α (TNF-α) inhibitor lenalidomide (10 mg/kg), followed by observation of lung injury status through hematoxylin and eosin staining and detection of neutrophil infiltration levels through naphthol esterase and Ly6G immunohistochemical staining. Additionally, peripheral blood polymorphonuclear neutrophils (PMNs) were cultured in vitro and then stimulated by TNF-α to mimic in vivo inflammatory stimuli; this TNF-α stimulation was also performed on PMNs after knockdown of FoxO3a or treatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125. PMN apoptosis after stimulation was detected using flow cytometry. Finally, the role of PMN apoptosis in IIR-induced lung injury was evaluated in vivo by detecting the ALI status in the model mice administered with ABT-199, a Bcl-2 inhibitor.ResultsIIR led to pulmonary histopathological injury and increased lung water content, which were accompanied by increased plasma levels of inflammatory factors, with the TNF-α plasma level showing the most pronounced increase. Inhibition of TNF-α led to effective reduction of lung tissue injury, especially that of the damaging infiltration of PMNs in the lung. In vitro knockdown of FoxO3a or inhibition of JNK activity could inhibit TNF-α-induced PMN apoptosis. Further in vivo experiments revealed that ABT-199 effectively alleviated lung injury and decreased inflammation levels by promoting PMN apoptosis during IIR-induced lung injury.ConclusionTNF-α activates the JNK/FoxO3a pathway to induce a delay in PMN apoptosis, which promotes IIR-induced lung injury.

Dataset Information

Inhibition of ANO1/TMEM16A induces apoptosis in human prostate carcinoma cells by activating TNF-? signaling.

Publications

Inhibition of ANO1/TMEM16A induces apoptosis in human prostate carcinoma cells by activating TNF-α signaling.

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