The Vacuolar ATPase a2-subunit regulates Notch signaling in triple-negative breast cancer cells

Pamarthy, Sahithi; Jaiswal, Mukesh K.; Kulshreshtha, Arpita; Katara, Gajendra K.; Gilman‐Sachs, Alice; Beaman, Kenneth D.

doi:10.18632/oncotarget.5275

Cited by 31 publications

(27 citation statements)

References 63 publications

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“…However, contrary to these previous studies, it was recently reported that inhibition of the V-ATPase increased Notch signaling in triple negative breast cancers. In this case, a similar accumulation of Notch receptors due to loss of lysosomal degradation is observed, but the consequence of this accumulation is persistent Notch signaling (143). Further studies will clarify the factors underlying this difference.…”

Section: V-atpase and Notch Signalingmentioning

confidence: 55%

“…Cathepsins are proteases that normally reside in lysosomes and that require a low pH for both their activity and their proteolytic activation (115,180,190), while MMPs, although not directly pH dependent, can nevertheless be activated at low pH, in particular by cathepsin-dependent cleavage (83,166,190). Both cathepsins and MMPs are secreted by tumor cells and have been shown to participate in invasion (8,54,110,115,143,185). Moreover, both intracellular and plasma membrane V-ATPases may contribute to the promotion of protease activity.…”

Section: Mechanism Of V-atpase Promotion Of Tumor Cell Invasion Anmentioning

confidence: 99%

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The Function of V-ATPases in Cancer

Stransky

Cotter

Forgac

2016

Physiological Reviews

238

268

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The vacuolar ATPases (V-ATPases) are a family of proton pumps that couple ATP hydrolysis to proton transport into intracellular compartments and across the plasma membrane. They function in a wide array of normal cellular processes, including membrane traffic, protein processing and degradation, and the coupled transport of small molecules, as well as such physiological processes as urinary acidification and bone resorption. The V-ATPases have also been implicated in a number of disease processes, including viral infection, renal disease, and bone resorption defects. This review is focused on the growing evidence for the important role of V-ATPases in cancer. This includes functions in cellular signaling (particularly Wnt, Notch, and mTOR signaling), cancer cell survival in the highly acidic environment of tumors, aiding the development of drug resistance, as well as crucial roles in tumor cell invasion, migration, and metastasis. Of greatest excitement is evidence that at least some tumors express isoforms of V-ATPase subunits whose disruption is not lethal, leading to the possibility of developing anti-cancer therapeutics that selectively target V-ATPases that function in cancer cells.

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Section: V-atpase and Notch Signalingmentioning

confidence: 55%

Section: Mechanism Of V-atpase Promotion Of Tumor Cell Invasion Anmentioning

confidence: 99%

The Function of V-ATPases in Cancer

Stransky

Cotter

Forgac

2016

Physiological Reviews

238

268

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“…For example, in some systems, V‐ATPase is required for optimal signaling downstream of NOTCH receptors as V‐ATPase‐mediated acidification of endosomes enhances γ‐secretase‐mediated proteolysis of NOTCH to generate the active NICD cleavage product 4, 5. However, in other cell systems (ie, triple negative breast cancer cells) V‐ATPase appears to negatively regulate NOTCH signaling as chemical inhibition of V‐ATPase activity or RNAi‐mediated knockdown of the V o a2 subunit, results in increased NOTCH signaling associated with increased NICD expression 6. Consistent with this inhibitory effect, conditional deletion of V o a2 in mouse mammary glands results in reduced mammary gland development, associated with increased NOTCH (and TGFβ) signaling 7.…”

Section: V‐atpase Structure and Function In Normal Physiologymentioning

confidence: 99%

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

et al. 2018

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Vacuolar ATPase (V‐ATPase) is an ATP‐dependent H+‐transporter that pumps protons across intracellular and plasma membranes. It consists of a large multi‐subunit protein complex and influences a wide range of cellular processes. This review focuses on emerging evidence for the roles for V‐ATPase in cancer. This includes how V‐ATPase dysregulation contributes to cancer growth, metastasis, invasion and proliferation, and the potential link between V‐ATPase and the development of drug resistance.

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“…7, 9 We previously reported that a2V inhibition in breast cancer cell lines affects notch receptor processing and results in aberrant activation of the Notch pathway. 26 Our finding that a2V is expressed on the plasma membrane of luminal cells led us to investigate the expression of Notch 1 in a2V-KO mice. First, we performed double immunofluorescence for luminal epithelial marker CK18 and basal epithelial marker CK14.…”

Section: Resultsmentioning

confidence: 99%

“…24, 25 We have previously reported that a2V regulates lysosomal degradation of Notch receptor Notch 1 and alters Notch signaling in breast cancer. 26 Similarly, a2V regulates Notch signaling in inflammation-induced preterm labor in mice. 27 However, the involvement of a2V in context of Notch and TGF- β pathways in mammary gland development has not been explored.…”

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confidence: 99%

The V-ATPase a2 isoform controls mammary gland development through Notch and TGF-β signaling

et al. 2016

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Among all tissues and organs, the mammary gland is unique because most of its development occurs in adulthood. Notch signaling has a major role in mammary gland development and has been implicated in breast cancer. The vacuolar-ATPase (V-ATPase) is a proton pump responsible for the regulation and control of pH in intracellular vesicles and the extracellular milieu. We have previously reported that a2V-ATPase (a2V), an isoform of ‘a' subunit of V-ATPase, regulates processing of Notch receptor and alters Notch signaling in breast cancer. To study the role of a2V in mammary gland development, we generated an a2V-KO model (conditional mammary knockout a2V mouse strain). During normal mammary gland development, the basal level expression of a2V increased from puberty, virginity, and pregnancy through the lactation stage and then decreased during involution. Litters of a2V-KO mice weighed significantly less when compared with litters from wild-type mice and showed reduced expression of the lactation marker β-casein. Whole-mount analysis of mammary glands demonstrated impaired ductal elongation and bifurcation in a2V-KO mice. Consequently, we found disintegrated mammary epithelium as seen by basal and luminal epithelial staining, although the rate of proliferation remained unchanged. Delayed mammary morphogenesis in a2V-KO mice was associated with aberrant activation of Notch and TGF-β (transforming growth factor-β) pathways. Notably, Hey1 (hairy/enhancer-of-split related with YRPW motif) and Smad2, the key downstream mediators of Notch and TGF-β pathways, respectively, were upregulated in a2V-KO mice and also in human mammary epithelial cells treated with a2V siRNA. Taken together, our results show that a2V deficiency disrupts the endolysosomal route in Notch and TGF signaling, thereby impairing mammary gland development. Our findings have broader implications in developmental and oncogenic cellular environments where V-ATPase, Notch and TGF-β are crucial for cell survival.

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The Vacuolar ATPase a2-subunit regulates Notch signaling in triple-negative breast cancer cells

Cited by 31 publications

References 63 publications

The Function of V-ATPases in Cancer

The Function of V-ATPases in Cancer

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

The V-ATPase a2 isoform controls mammary gland development through Notch and TGF-β signaling

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