Oncotarget

Research Papers:

Osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity

Matthew McConnell, Shengmei Feng, Wei Chen, Guochun Zhu, Dejun Shen, Selvarangan Ponnazhagan, Lianfu Deng and Yi-Ping Li _

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Oncotarget. 2017; 8:47675-47690. https://doi.org/10.18632/oncotarget.17544

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Abstract

Matthew McConnell1,*, Shengmei Feng1,2,*, Wei Chen1, Guochun Zhu2, Dejun Shen1, Selvarangan Ponnazhagan1, Lianfu Deng2 and Yi-Ping Li1

1Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

2Shanghai Institute of Traumatology and Orthopedics, 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

*These authors have contributed equally to this work

Correspondence to:

Yi-Ping Li, email: ypli@uab.edu

Lianfu Deng, email: lf_deng@126.com

Keywords: Atp6v1c1, breast cancer, mTOR, tumor growth, metastasis

Received: November 04, 2016     Accepted: December 15, 2016     Published: May 02, 2017

ABSTRACT

It is known that V-ATPases (vacuolar H+-ATPase) are involved in breast cancer growth and metastasis. Part of this action is similar to their role in osteoclasts, where they’re involved in extracellular acidification and matrix destruction; however, the roles of their subunits in cancer cell proliferation, signaling, and other pro-tumor actions are not well established. Analysis of TCGA data shows that V-ATPase subunit Atp6v1c1 is overexpressed or amplified in 34% of human breast cancer cases, with a 2-fold decrease in survival at 12 years. Whereas other subunits, such as Atp6v1c2 and Atp6v0a3, are overexpressed or genomically amplified less often, 6% each respectively, and have less impact on survival. Experiments show that lentiviral-shRNA mediated ATP6v1c1 knockdown in 4T1 mouse mammary cancer cells significantly reduces orthotopic and intraosseous tumor growth. ATP6v1c1 knockdown also significantly reduces tumor stimulated bone resorption through osteoclastogenesis at the bone and metastasis in vivo, as well as V-ATPase activity, proliferation, and mTORC1 activation in vitro. To generalize the effects of ATP6v1c1 knockdown on proliferation and mTORC1 activation we used human cancer cell lines - MCF-7, MDA-MB-231, and MDA-MB-435s. ATP6V1C1 knockdown reduced cell proliferation and impaired mTORC1 pathway activation in cancer cells but not in the untransformed cell line C3H10T1/2. Our study reveals that V-ATPase activity may be mediated through mTORC1 and that ATP6v1c1 can be knocked down to block both V-ATPase and mTORC1 activity.


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