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Anticancer Effect of Verteporfin on Non-Small Cell Lung Cancer via Gradual Reduction of ANO1 Protein Levels
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  • Sung Baek Jeong,
  • Raju Das,
  • Dong-hyun Kim,
  • Sion Lee,
  • Hye In Oh,
  • Sungwoo Jo,
  • Jeongdong Kim,
  • SeonJu Park,
  • Uk Yeol Moon,
  • Oh-bin Kwon,
  • Wan Namkung,
  • Sungwoo Lee,
  • Byoung Chul Cho,
  • Joohan Woo,
  • Yohan Seo
Sung Baek Jeong
Daegu-Gyeongbuk Medical Innovation Foundation
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Raju Das
Dongguk University College of Medicine
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Dong-hyun Kim
Daegu-Gyeongbuk Medical Innovation Foundation
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Sion Lee
Daegu-Gyeongbuk Medical Innovation Foundation
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Hye In Oh
Yonsei University
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Sungwoo Jo
Yonsei University College of Pharmacy
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Jeongdong Kim
Yonsei University
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SeonJu Park
Korea Basic Science Institute
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Uk Yeol Moon
Daegu-Gyeongbuk Medical Innovation Foundation
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Oh-bin Kwon
Daegu-Gyeongbuk Medical Innovation Foundation
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Wan Namkung
Yonsei University College of Pharmacy
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Sungwoo Lee
Daegu-Gyeongbuk Medical Innovation Foundation
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Byoung Chul Cho
Yonsei University College of Medicine
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Joohan Woo
Dongguk University College of Medicine
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Yohan Seo
Daegu-Gyeongbuk Medical Innovation Foundation

Corresponding Author:[email protected]

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Abstract

Background and Purpose: 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. This study aimed to investigate whether verteporfin exerts anticancer effects on non-small cell lung cancer by gradually reducing ANO1 protein levels. Experimental Approach: We screened ANO1 inhibitors for biological activity using high-throughput screening and selected verteporfin. Subsequently, we investigated the effects of verteporfin on NSCLC cells as well as the molecular mechanisms involved. Key Results: Verteporfin reduced ANO1 protein levels but had no effects on its channel function. 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. Verteporfin inhibited neither P2Y receptor-induced intracellular Ca2+ mobilization nor cystic fibrosis transmembrane conductance regulator (CFTR) channel activity. Molecular docking studies revealed that verteporfin bound to specific sites on ANO1 protein. Interestingly, verteporfin decreased p-EGF receptor levels via reduction of ANO1 protein levels; however, it increased p-ERK1/2 levels. Verteporfin reduced the viability and migration of only ANO1-expressing cells, PC9, and gefitinib-resistant PC9 cells, and induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage; however, it did not affect hERG channel activity. Conclusion and Implications: These results indicate that the main mechanism underlying verteporfin action associated with anticancer activity involves the reduction of ANO1 protein levels.