Fluvastatin inhibits HMG-CoA reductase and prevents non-small cell lung carcinogenesi

Tianshun Zhang, Ruihua Bai, Qiushi Wang, Keke Wang, Xiang Li, Kangdong Liu, Joohyun Ryu, Ting Wang, Xiaoyu Chang, Weiya Ma, Ann M. Bode, Qingxin Xia, Yongping Song, Zigang Dong

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. However, promising agents for lung cancer prevention are still very limited. Identification of preventive targets and novel effective preventive agents is urgently needed for clinical applications. In this study, we found that fluvastatin targeted 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), which a rate-limiting enzyme in the mevalonate pathway, and inhibited non-small cell lung cancer (NSCLC) tumorigenesis. Initially, we demonstrated that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo. Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation.

Original languageEnglish (US)
Pages (from-to)837-848
Number of pages12
JournalCancer Prevention Research
Volume12
Issue number12
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
The authors thank Todd Schuster for supporting the experiments, Tara Adams for supporting animal experiments, and Becky Earl for assistance in submitting our article (The Hormel Institute, University of Minnesota, Minneapolis, MN). This work was supported by the Hormel Foundation (to Z. Dong).

Publisher Copyright:
© 2019 American Association for Cancer Research.

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