Int J Biol Sci 2013; 9(8):853-862. doi:10.7150/ijbs.6030
Silencing of Atp6v1c1 Prevents Breast Cancer Growth and Bone Metastasis
1. Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, P.R.China.
2. Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
* Authors contributed equally as first authors.
Previous studies have shown that Atp6v1c1, a regulator of the assembly of the V0 and V1 domains of the V-ATPase complex, is up-regulated in metastatic oral tumors. Despite these studies, the function of Atp6v1c1 in tumor growth and metastasis is still unknown. Atp6v1c1's expression in metastatic oral squamous cell carcinoma indicates that Atp6v1c1 has an important function in cancer growth and metastasis. We hypothesized that elevated expression of Atp6v1c1 is essential to cancer growth and metastasis and that Atp6v1c1 promotes cancer growth and metastasis through activation of V-ATPase activity. To test this hypothesis, a Lentivirus-mediated RNAi knockdown approach was used to study the function of Atp6v1c1 in mouse 4T1 mammary tumor cell proliferation and migration in vitro and cancer growth and metastasis in vivo. Our data revealed that silencing of Atp6v1c1 in 4T1 cancer cells inhibited lysosomal acidification and severely impaired 4T1 cell growth, migration, and invasion through Matrigel in vitro. We also show that Atp6v1c1 knockdown with Lenti-c1s3, a lentivirus targeting Atp6v1c1 for shRNA mediated knockdown, can significantly inhibit 4T1 xenograft tumor growth, metastasis, and osteolytic lesions in vivo. Our study demonstrates that Atp6v1c1 may promote breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity, indicating that Atp6v1c1 may be a viable target for breast cancer therapy and silencing of Atp6v1c1 may be an innovative therapeutic approach for the treatment and prevention of breast cancer growth and metastasis.
Keywords: Atp6v1c1 (C1), V-ATPase, breast cancer, lysosomal acidification, tumor bone metastasis.
Feng S, Zhu G, McConnell M, Deng L, Zhao Q, Wu M, Zhou Q, Wang J, Qi J, Li YP, Chen W. Silencing of Atp6v1c1 Prevents Breast Cancer Growth and Bone Metastasis. Int J Biol Sci 2013; 9(8):853-862. doi:10.7150/ijbs.6030. Available from http://www.ijbs.com/v09p0853.htm