Fluvastatin Prevents Lung Adenocarcinoma Bone Metastasis by Triggering Autophagy

• Published in: EBioMedicine 2017-05, Vol.19 (C), p.49-59
• Main Authors: Yang, Zuozhang, Su, Zhenyi, DeWitt, Judy Park, Xie, Lin, Chen, Yongbin, Li, Xiaojuan, Han, Lei, Li, Dongqi, Xia, Junfeng, Zhang, Ya, Yang, Yihao, Jin, Congguo, Zhang, Jing, Li, Su, Li, Kun, Zhang, Zhiping, Qu, Xin, He, Zewei, Chen, Yanjin, Shen, Yan, Ren, Mingyan, Yuan, Zhongqin
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Autophagy; Autophagy - drug effects; Bone Neoplasms - metabolism; Bone Neoplasms - prevention & control; Bone Neoplasms - secondary; Cell Line, Tumor; Fatty Acids, Monounsaturated - pharmacology; Fatty Acids, Monounsaturated - therapeutic use; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Indoles - pharmacology; Indoles - therapeutic use; Lung adenocarcinoma bone metastasis; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice, Inbred BALB C; Mice, Nude; p53; Research Paper; Statins; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.04.017

Bone is one of the most preferred sites of metastasis in lung cancer. Currently, bisphosphonates and denosumab are major agents for controlling tumor-associated skeletal-related events (SREs). However, both bisphosphonates and denosumab significantly increase the risk for jaw osteonecrosis. Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and the most frequently prescribed cholesterol-lowering agents, have been reported to inhibit tumor progression and induce autophagy in cancer cells. However, the effects of statin and role of autophagy by statin on bone metastasis are unknown. In this study, we report that fluvastatin effectively prevented lung adenocarcinoma bone metastasis in a nude mouse model. We further reveal that fluvastatin-induced anti-bone metastatic property was largely dependent on its ability to induce autophagy in lung adenocarcinoma cells. Atg5 or Atg7 deletion, or 3-methyadenine (3-MA) or Bafilomycin A1 (Baf A1) treatment prevented the fluvastatin-induced suppression of bone metastasis. Furthermore, we reveal that fluvastatin stimulation increased the nuclear p53 expression, and fluvastatin-induced autophagy and anti-bone metastatic activity were mostly dependent on p53. •Fluvastatin effectively prevents lung adenocarcinoma bone metastasis in a nude mouse model.•Fluvastatin-induced anti-bone metastatic property was largely dependent on its ability to induce autophagy.•Fluvastatin-induced autophagy and anti-bone metastatic activity are mediated by p53. Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are most frequently prescribed cholesterol-lowering agent with minimal side effects. In this study, we present a novel function of statins in suppressing lung adenocarcinoma bone metastasis, and this function is dependent on statin-induced autophagy. Currently, there is no cure for bone metastasis, and the current treatment options using anti-bone metastatic agents have negative side effects. For example, bisphosphonates or denosumab treatments reduce tumor-associated skeletal-related events, but simultaneously increase the risk of the osteonecrosis in the jaw. As a possible therapeutic treatment option, fluvastatin is promising to cancer patients with a high risk of bone metastasis.