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.
Highlights
The multi-subunit V-ATPase complex is composed of an ATP-hydrolytic domain (V1) and a membrane spanning proton-translocation domain (V0), along with two accessory subunits ac45 and M8-9 [1]
In order to provide an initial assessment of the dysregulation of ATP6v1c1 we examined TCGA data on its expression and amplification, which we used as a proxy to indicate the potential for a clinically relevant role for those subunits and their dysregulation in human breast cancer, as through oncogene addiction [37]
We examined the extent of dysregulation and especially amplification of Atp6v1c2 and Atp6v0a3 in patient samples using data from TCGA (Supplementary Figure 1) and, relative to ATP6v1c1 (Figure 1), their amplification and overexpression was considerably less common and, even where present, didn’t have a significant effect on patient survival
Summary
The multi-subunit V-ATPase complex is composed of an ATP-hydrolytic domain (V1) and a membrane spanning proton-translocation domain (V0), along with two accessory subunits ac and M8-9 [1]. The V-ATPases have long been known to have roles in cancer [10,11,12,13], in addition to their originally characterized functions in acidifying lysosomal vacuoles They are known to activate acid dependent lysosomal proteases and known for their role in osteoclast mediated www.impactjournals.com/oncotarget bone resorption, as well as a role that has been suggested to be similar to the formation of invadopodia of invasive tumor cells [9, 14, 15]. It remains unclear which subunits may be dysregulated in which cancers and which, if any, could be targeted for cancer therapy [9]
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