Inhibition of ANO1/TMEM16A induces apoptosis in human prostate carcinoma cells by activating TNF-α 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-α expression in prostate cancer PC-3 cells. Enhancement of TNF-α 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-α signaling. Taken together, our findings provide mechanistic insight into promoting apoptosis in prostate cancer cells by ANO1 inhibition through upregulation of TNF-α signaling.

Biochemical Inhibition of DOG1/TMEM16A Achieves Antitumoral Effects in Human Gastrointestinal Stromal Tumor Cells In Vitro

“…activated through TNF-α was similar between the knockdown model and a biochemical inhibition (23). In GIST, high DOG1 expression is associated with poor prognosis and its high levels in circulating tumor cells can predict recurrence (26).…”

“…In general, CaCC inh -A01 potently reduced cell viability in both cell lines, while T16 inh -A01 was more cell-specific, reducing viability more in GIST-T1 compared to GIST882. We used fully supplemented medium for viability assays in this study in contrast to another study using serum-starved cells with more potent effects on cell viability of DOG1 inhibition in prostate cancer with CaCC inh -A01 and T16 inh -A01 inhibitors (23). Using serum-starvation (no FBS added to cell medium), 30 μM CaCC inh -A01 had the best effect, and reduced cell viability by more than 50% over a 24-h time period in GIST-T1 cells (data not shown).…”

“…It was also shown that protein degradation was ER-associated and that the effect of degradation was observed after 24-48 hours. A study on prostate cancer has shown that DOG1 inhibitors could induce apoptosis in prostate cancer cell lines through upregulating TNF-α signaling (23). TNF-α signaling occured using both siRNA technology and biochemical inhibition using DOG1 inhibitors, suggesting similar mechanisms of action.…”

TRPV4 and purinergic receptor signalling pathways are separately linked in airway epithelia to CFTR and TMEM16A chloride channels

“…In our study, we investigated the mechanism of action of Eact, a putative activator of the TMEM16A chloride channel. Eact, which was initially discovered by its high efficacy in FRT cells expressing TMEM16A (Namkung et al 2011b), has been used in many studies to demonstrate the role of TMEM16A in transepithelial ion transport, smooth muscle contraction, endocrine function, mucus release and cell proliferation and migration (Namkung et al 2011b;Berglund et al 2014;Sun et al 2014;Allawzi et al 2018;Song et al 2018;Benedetto et al 2019). In contrast with Eact being a direct activator of TMEM16A, we found little effect of this compound in bronchial epithelial cells under conditions of high TMEM16A expression, i.e.…”

TMEM16A regulates the cell cycle of pulmonary artery smooth muscle cells in high‑flow‑induced pulmonary arterial hypertension rat model

“…In addition, studies addressing the TMEM16A-mediated regulation of protein expression that is associated with cell cycle progression, particularly the effect of TMEM16A knockout in vivo, are urgently required. Finally, specific signaling pathways, including ERK/cyclin D1 (31) and/or cyclin D1-MARK (32)(33)(34), serve as potential targets for future studies.…”