ArticleMolecular oncology2016
Selective inhibition of tumor cell associated Vacuolar-ATPase 'a2' isoform overcomes cisplatin resistance in ovarian cancer cells.
Article in Molecular oncology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 38 citations in OpenAlex.
- FAM172A promotes epithelial ovarian cancer progression and induces platinum resistance via the PI3K/AKT pathway.Scientific reports · 2025Article
- Endosomal Mechanisms in Heart Failure Pathophysiology.Current heart failure reports · 2025Review
- Proteomic Landscapes of 3D and 2D Models of High-Grade Serous Ovarian Carcinoma: Implications for Carboplatin Response.Journal of proteome research · 2025Article
- The Role of V-ATPase ATP6V0D1 Subunit in Chemoresistance and Ellipticine-Induced Cytoplasmic Vacuolation in Neuroblastoma Cells.Molecular & cellular oncology · 2025Article
- A nanobody against the V-ATPase c subunit inhibits metastasis of 4T1-12B breast tumor cells to lung in mice.Oncotarget · 2024Article
- ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8Nature communications · 2024Article
- The V-ATPases in cancer and cell death.Cancer gene therapy · 2022Review
- PHY34 inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer.Cell death & disease · 2022Article
- Multifactorial Mechanisms of Tolerance to Ketoconazole in Candida albicans.Microbiology spectrum · 2021Article
- The Golgi as a "Proton Sink" in Cancer.Frontiers in cell and developmental biology · 2021Article
- Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy.Journal of translational medicine · 2020Article
- In vivo anti-V-ATPase antibody treatment delays ovarian tumor growth by increasing antitumor immune responses.Molecular oncology · 2020Article
- Article
- Cancer-associated V-ATPase induces delayed apoptosis of protumorigenic neutrophils.Molecular oncology · 2020Article
- Proton pump inhibitors can reverse the YAP mediated paclitaxel resistance in epithelial ovarian cancer.BMC molecular and cell biology · 2019Article
- Specific V-ATPase expression sub-classifies IDHwt lower-grade gliomas and impacts glioma growth in vivo.EBioMedicine · 2019Article
- Targeting V-ATPase Isoform Restores Cisplatin Activity in Resistant Ovarian Cancer: Inhibition of Autophagy, Endosome Function, and ERK/MEK Pathway.Journal of oncology · 2019Article
- V-ATPase in cancer progression: Two sides of the same coin.Oncotarget · 2018Article
- Phyllanthusmin Derivatives Induce Apoptosis and Reduce Tumor Burden in High-Grade Serous Ovarian Cancer by Late-Stage Autophagy Inhibition.Molecular cancer therapeutics · 2018Article
- Hematopoietic stem cell specific V-ATPase controls breast cancer progression and metastasis via cytotoxic T cells.Oncotarget · 2018Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Development of resistance to platinum compounds significantly hinders successful ovarian cancer (OVCA) treatment. In tumor cells, dysregulated pH gradient across cell membranes is a key physiological mechanism of metastasis/chemo-resistance. These pH alterations are mediated by aberrant activation of key multi-subunit proton pumps, Vacuolar-ATPases (V-ATPases). In tumor cells, its 'a2' isoform (V-ATPase-V0a2) is a component of functional plasma-membrane complex and promotes tumor invasion through tumor-acidification and immuno-modulation. Its involvement in chemo-resistance has not been studied. Here, we show that V-ATPase-V0a2 is over-expressed in acquired-cisplatin resistant OVCA cells (cis-A2780/cis-TOV112D). Of all the 'a' subunit isoforms, V-ATPase-V0a2 exhibited an elevated expression on plasma membrane of cisplatin-resistant cells compared to sensitive counterparts. Immuno-histochemistry revealed V-ATPase-V0a2 expression in both low grade (highly drug-resistant) and high grade (highly recurrent) human OVCA tissues indicating its role in a centralized mechanism of tumor resistance. In cisplatin resistant cells, shRNA mediated inhibition of V-ATPase-V0a2 enhanced sensitivity towards both cisplatin and carboplatin. This improved cytotoxicity was mediated by enhanced cisplatin-DNA-adduct formation and suppressed DNA-repair pathway, leading to enhanced apoptosis. Suppression of V0a2 activity strongly reduced cytosolic pH in resistant tumor cells, which is known to enhance platinum-associated DNA-damage. As an indicator of reduced metastasis and chemo-resistance, in contrast to plasma membrane localization, a diffused cytoplasmic localization of acidic vacuoles was observed in V0a2-knockdown resistant cells. Interestingly, pre-treatment with monoclonal V0a2-inhibitory antibody enhanced cisplatin cytotoxicity in resistant cells. Taken together, our findings suggest that the isoform specific inhibition of V-ATPase-V0a2 could serve as a therapeutic strategy for chemo-resistant ovarian carcinoma and improve efficacy of platinum drugs.
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