Fluvastatin Inhibits HMG-CoA Reductase and Prevents Non-Small Cell Lung Carcinogenesis.

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.

• Authors: 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
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 12 Issue 12 Pg. 837-848 (Dec 2019) ISSN: 1940-6215 [Electronic] United States
• PMID: 31554629 (Publication Type: Journal Article)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Acyl Coenzyme A
• Carcinogens
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Nitrosamines
• RNA, Small Interfering
• 3-hydroxy-3-methylglutaryl-coenzyme A
• Fluvastatin
• 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
• HMGCR protein, human
• Hydroxymethylglutaryl CoA Reductases
• Mevalonic Acid

Topics

• Acyl Coenzyme A (metabolism)
• Adult
• Aged
• Animals
• Apoptosis (drug effects)
• Carcinogenesis (drug effects)
• Carcinogens (toxicity)
• Carcinoma, Non-Small-Cell Lung (pathology, prevention & control)
• Cell Line, Tumor
• Female
• Fluvastatin (pharmacology, therapeutic use)
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• Hydroxymethylglutaryl CoA Reductases (genetics, metabolism)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Lung (pathology)
• Lung Neoplasms (pathology, prevention & control)
• Male
• Mevalonic Acid (metabolism)
• Mice
• Middle Aged
• Neoplasms, Experimental (chemically induced, drug therapy, pathology)
• Nitrosamines (toxicity)
• RNA, Small Interfering (metabolism)
• Xenograft Model Antitumor Assays