Anticancer effect of verteporfin on non-small cell lung cancer via downregulation of ANO1.

Abstract

Anoctamin 1 (ANO1) is a calcium-activated chloride channel found in various cell types and is overexpressed in non-small cell lung cancer (NSCLC), a major cause of cancer-related mortality. With the rising interest in development of druggable compounds for NSCLC, there has been a corresponding rise in interest in ANO1, a novel drug target for NSCLC. However, as ANO1 inhibitors that have been discovered simultaneously exhibit both the functions of an inhibition of ANO1 channel as well as a reduction of ANO1 protein levels, it is unclear which of the two functions directly causes the anticancer effect. In this study, verteporfin, a chemical compound that reduces ANO1 protein levels was identified through high-throughput screening. Verteporfin did not inhibit ANO1-induced chloride secretion but reduced ANO1 protein levels in a dose-dependent manner with an IC50 value of ~300 nM. Moreover, verteporfin inhibited neither P2Y receptor-induced intracellular Ca2+ mobilization nor cystic fibrosis transmembrane conductance regulator (CFTR) channel activity, and molecular docking studies revealed that verteporfin bound to specific sites of ANO1 protein. Confirming that verteporfin reduces ANO1 protein levels, we then investigated the molecular mechanisms involved in its effect on NSCLC cells. Interestingly, verteporfin decreased ANO1 protein levels, the EGFR-STAT3 pathway as well as ANO1 mRNA expression. Verteporfin reduced the viability of ANO1-expressing cells (PC9, and gefitinib-resistant PC9) and induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage. However, it did not affect hERG channel activity. These results show that the anticancer mechanism of verteporfin is caused via the down-regulation of ANO1.

• Authors: Sung Baek Jeong, Raju Das, Dong-Hyun Kim, Sion Lee, Hye In Oh, Sungwoo Jo, Yechan Lee, Jeongdong Kim, SeonJu Park, Dong Kyu Choi, Uk Yeol Moon, Oh-Bin Kwon, Wan Namkung, Sungwoo Lee, Byoung Chul Cho, Joohan Woo, Yohan Seo
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 153 Pg. 113373 (Sep 2022) ISSN: 1950-6007 [Electronic] France
• PMID: 35785700 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• ANO1 protein, human
• Anoctamin-1
• Chloride Channels
• Neoplasm Proteins
• Verteporfin
• Calcium

Topics

• Anoctamin-1 (genetics, metabolism)
• Calcium (metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Chloride Channels (metabolism)
• Down-Regulation
• Humans
• Lung Neoplasms (drug therapy)
• Molecular Docking Simulation
• Neoplasm Proteins (genetics, metabolism)
• Verteporfin (pharmacology)