Fluvastatin Prevents Lung Adenocarcinoma Bone Metastasis by Triggering Autophagy

Zuozhang Yang  ¹ , Zhenyi Su  ² , Judy Park DeWitt  ³ , Lin Xie  ⁴ , Yongbin Chen  ⁵ , Xiaojuan Li  ⁶ , Lei Han  ⁶ , Dongqi Li  ⁶ , Junfeng Xia  ⁶ , Ya Zhang  ⁶ , Yihao Yang  ⁶ , Congguo Jin  ⁷ , Jing Zhang  ⁶ , Su Li  ⁶ , Kun Li  ⁸ , Zhiping Zhang  ⁸ , Xin Qu  ⁶ , Zewei He  ⁶ , Yanjin Chen  ⁶ , Yan Shen  ⁴ , Mingyan Ren  ⁴ , Zhongqin Yuan  ⁴

Affiliations

• ¹ Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118, China. Electronic address: yangzuozhang@163.com.
• ² Department of Biochemistry and Molecular Biology, Medical School, Southeast University, Nanjing, Jiangsu 210009, China; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: suzhenyi999@163.com.
• ³ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
• ⁴ Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118, China.
• ⁵ Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
• ⁶ Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118, China.
• ⁷ Cancer Institute, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118, China.
• ⁸ Department of Radiology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118, China.

Abstract

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.

Keywords: Autophagy; Fluvastatin; Lung adenocarcinoma bone metastasis; Statins; p53.