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.
Highlights
Prostate cancer originates from the glandular epithelial cells, and is one of the most common malignancies and the second leading cause of cancer-related death in males worldwide[1]
Suppression of ANO1 overexpression inhibits cell growth and induces apoptosis in prostate cancer PC-3 cells To investigate the biological function of ANO1, we compared the protein and mRNA levels of ANO1 in normal prostate epithelial cells (RWPE-1) and prostate cancer cell lines (DU145, LNCaP, 22RV1, VCaP, and PC3)
Cell death analysis revealed that ANO1 silencing induced marked apoptosis, which could be blocked with a pan-caspase inhibitor (Z-VAD-FMK34, Fig. 2c)
Summary
Prostate cancer originates from the glandular epithelial cells, and is one of the most common malignancies and the second leading cause of cancer-related death in males worldwide[1]. ANO1 overexpression is involved in the tumorigenesis of epithelial cancers including oral cancer[4], gastrointestinal stromal tumor (GIST)[5], head and neck squamous cell carcinoma (HNSCC)[6], prostate cancer[7] and hyperplasia[8], breast cancer[9], colorectal cancer[10], glioma[11], ANO1 gene is located within the chromosome 11q13 that is one of the most frequently amplified regions in human cancer and associated with poor prognosis[16,17,18,19]. Silencing or inhibition of ANO1 suppresses proliferation, metastasis, and invasion of cancer cells[7,14,21,22,23], and promotes GIST cells to undergo apoptosis[24]. How ANO1 inhibition exerts anti-tumor activity or causes apoptosis in cancer cells remains unknown
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