Diethylstilbestrol, a Novel ANO1 Inhibitor, Exerts an Anticancer Effect on Non-Small Cell Lung Cancer via Inhibition of ANO1.

Abstract

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality; thus, therapeutic targets continue to be developed. Anoctamin1 (ANO1), a novel drug target considered for the treatment of NSCLC, is a Ca2+-activated chloride channel (CaCC) overexpressed in various carcinomas. It plays an important role in the development of cancer; however, the role of ANO1 in NSCLC is unclear. In this study, diethylstilbestrol (DES) was identified as a selective ANO1 inhibitor using high-throughput screening. We found that DES inhibited yellow fluorescent protein (YFP) fluorescence reduction caused by ANO1 activation but did not inhibit cystic fibrosis transmembrane conductance regulator channel activity or P2Y activation-related cytosolic Ca2+ levels. Additionally, electrophysiological analyses showed that DES significantly reduced ANO1 channel activity, but it more potently reduced ANO1 protein levels. DES also inhibited the viability and migration of PC9 cells via the reduction in ANO1, phospho-ERK1/2, and phospho-EGFR levels. Moreover, DES induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage in PC9 cells, but it did not affect the viability of hepatocytes. These results suggest that ANO1 is a crucial target in the treatment of NSCLC, and DES may be developed as a potential anti-NSCLC therapeutic agent.

• Authors: Yohan Seo, Sung Baek Jeong, Joo Han Woo, Oh-Bin Kwon, Sion Lee, Hye In Oh, Sungwoo Jo, Seon Ju Park, Wan Namkung, Uk Yeol Moon, Sungwoo Lee
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 13 (Jul 01 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34281152 (Publication Type: Journal Article)

Chemical References

• ANO1 protein, human
• Anoctamin-1
• CFTR protein, human
• Neoplasm Proteins
• Cystic Fibrosis Transmembrane Conductance Regulator
• Diethylstilbestrol

Topics

• Anoctamin-1 (antagonists & inhibitors, metabolism)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics, metabolism)
• Diethylstilbestrol (metabolism, pharmacology)
• Humans
• Lung Neoplasms
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Signal Transduction