The V-ATPases in cancer and cell death

Chen, Fangquan; Kang, Rui; Liu, Jiao; Tang, Daolin

doi:10.1038/s41417-022-00477-y

Cited by 56 publications

(34 citation statements)

References 187 publications

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“…71,72 Besides, the role of pH regulators, including MCT1, NHE1, CAIX, and V-ATPase, has been reported in the acidification of TME. [41][42][43] Our results…”

Section: Discussionsupporting

confidence: 55%

“…Tumor acidosis has been widely noted in most cancers, including malignancy of T cells 29,39 . Further, experimental evidence suggests an indispensable role of pH regulatory molecules, particularly V‐ATPase, CAIX, NHE1, and MCT1, in maintaining dysregulated pH in tumor cells 40–43 . Hence, next, we analyzed if SDF administration to mice having T cell lymphoma can alter the pH homeostasis.…”

Section: Resultsmentioning

confidence: 99%

“…29,39 Further, experimental evidence suggests an indispensable role of pH regulatory molecules, particularly V-ATPase, CAIX, NHE1, and MCT1, in maintaining dysregulated pH in tumor cells. [40][41][42][43] Hence, next, we analyzed if SDF administration to mice having T cell lymphoma can alter the pH homeostasis. Tumor cells (1 Â 10 6 cells/mL) and ascitic fluid were isolated from untreated control and SDF groups.…”

Section: Sdf Administration Alters the Ph Homeostasis Of Tumor Cellsmentioning

confidence: 99%

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Blockade of phosphodiesterase 5 by sildenafil reduces tumor growth and potentiates tumor‐killing ability of cisplatin in vivo against T cell lymphoma: Implication of modulated apoptosis, reactive oxygen species homeostasis, glucose metabolism, and pH regulation

Rawat,

Tiwari,

Kumar

2023

Environmental Toxicology

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In the past years, PDE5 has emerged as a promising therapeutic target for many cancers due to its highly upregulated expression. Interestingly, a recent in vitro study by our group has shown the antitumor and chemopotentiating action of sildenafil against T cell lymphoma. Our study showed that lower doses of sildenafil (50 μM) and cisplatin (0.5 μg/mL) exhibited 4% and 23% cytotoxicity against HuT78 cells, respectively, which was dramatically increased up to 50% when treated with both. Hence, the present study was designed to evaluate the antitumor and chemo‐potentiating action of sildenafil in a murine model of T cell lymphoma (popularly called as Dalton's lymphoma [DL]). In the present study, DL‐bearing mice were administered with vehicle (PBS), sildenafil (5 mg/kg bw), cisplatin (5 mg/kg bw), and sildenafil and cisplatin followed by evaluation of their impact on tumor growth by analyzing various parameters. The apoptosis was assessed by Wright–Giemsa, annexin‐V, and DAPI staining. Reactive oxygen species (ROS) level was examined through DCFDA staining. The expression of genes and proteins were estimated by RT‐PCR and Western blotting, respectively. The experimental findings of the study demonstrate for the first time that sildenafil inhibits tumor growth and potentiates tumor inhibitory ability of cisplatin by altering apoptosis, glycolysis, ROS homeostasis, and pH regulation in T cell lymphoma‐carrying host. In addition, our investigation also showed amelioration of tumor‐induced liver and kidney damage by sildenafil. Overall, the experimental data of our study strongly advocate the use and repurposing of SDF in designing promising chemotherapeutic regimens against malignancies of T cells.

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“…71,72 Besides, the role of pH regulators, including MCT1, NHE1, CAIX, and V-ATPase, has been reported in the acidification of TME. [41][42][43] Our results…”

Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Sdf Administration Alters the Ph Homeostasis Of Tumor Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Blockade of phosphodiesterase 5 by sildenafil reduces tumor growth and potentiates tumor‐killing ability of cisplatin in vivo against T cell lymphoma: Implication of modulated apoptosis, reactive oxygen species homeostasis, glucose metabolism, and pH regulation

Rawat,

Tiwari,

Kumar

2023

Environmental Toxicology

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“…A Molecular structures of the vATPase domains (subunits): V 0 (a-e) and V 1 (A-H). Redrawn from Chen et al [ 23 ]. B Expression analysis of vATPase subunits at different developmental stages.…”

Section: Resultsmentioning

confidence: 99%

“… Redrawn from Chen et al [ 23 ]. B Expression analysis of vATPase subunits at different developmental stages.…”

Section: Resultsmentioning

confidence: 99%

Greenhouse test of spraying dsRNA to control the western flower thrips, Frankliniella occidentalis, infesting hot peppers

Khan

Kim²,

Kim

2023

BMC Biotechnol

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Background The western flower thrips Frankliniella occidentalis is an insect pest that damages various crops, including hot peppers. It is a vector of a plant pathogen, tomato spotted wilt virus. To control this pest, chemical insecticides have been used in the past, but the control efficacy is unsatisfactory owing to rapid resistance development by F. occidentalis. Methodology : This study reports a novel control technology against this insect pest using RNA interference (RNAi) of the vacuolar-type ATPase (vATPase) expression. Eight subunit genes (vATPase-A ∼ vATPase-H) of vATPase were obtained from the F. occidentalis genome and confirmed for their expressions at all developmental stages. Results Double-stranded RNAs (dsRNAs) specific to the eight subunit genes were fed to larvae and adults, which significantly suppressed the corresponding gene expressions after 24-h feeding treatment. These RNAi treatments resulted in significant mortalities, in which the dsRNA treatments at ∼2,000 ppm specific to vATPase-A or vATPase-B allowed complete control efficacy near 100% mortality in 7 days after treatment. To prevent dsRNA degradation by the digestive proteases during oral feeding, dsRNAs were formulated in a liposome and led to an enhanced mortality of the larvae and adults of F. occidentalis. The dsRNAs were then sprayed at 2,000 ppm on F. occidentalis infesting hot peppers in a greenhouse, which resulted in 53.5–55.9% control efficacy in 7 days after treatment. Even though the vATPases are conserved in different organisms, the dsRNA treatment was relatively safe for non-target insects owing to the presence of mismatch sequences compared to the dsRNA region of F. occidentalis. Conclusion These results demonstrate the practical feasibility of spraying dsRNA to control F. occidentalis infesting crops.

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Alkaliptosis induction counteracts paclitaxel‐resistant ovarian cancer cells via ATP6V0D1‐mediated ABCB1 inhibition

Chen,

Lin,

Kang

et al. 2024

Molecular Carcinogenesis

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Paclitaxel serves as the cornerstone chemotherapy for ovarian cancer, yet its prolonged administration frequently culminates in drug resistance, presenting a substantial challenge. Here we reported that inducing alkaliptosis, rather than apoptosis or ferroptosis, effectively overcomes paclitaxel resistance. Mechanistically, ATPase H+ transporting V0 subunit D1 (ATP6V0D1), a key regulator of alkaliptosis, plays a pivotal role by mediating the downregulation of ATP‐binding cassette subfamily B member 1 (ABCB1), a multidrug resistance protein. Both ATP6V0D1 overexpression through gene transfection and pharmacological enhancement of ATP6V0D1 protein stability using JTC801 effectively inhibit ABCB1 upregulation, resulting in growth inhibition in drug‐resistant cells. Additionally, increasing intracellular pH to alkaline (pH 8.5) via sodium hydroxide application suppresses ABCB1 expression, whereas reducing the pH to acidic conditions (pH 6.5) with hydrochloric acid amplifies ABCB1 expression in drug‐resistant cells. Collectively, these results indicate a potentially effective therapeutic strategy for targeting paclitaxel‐resistant ovarian cancer by inducing ATP6V0D1‐dependent alkaliptosis.

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The V-ATPases in cancer and cell death

Cited by 56 publications

References 187 publications

Blockade of phosphodiesterase 5 by sildenafil reduces tumor growth and potentiates tumor‐killing ability of cisplatin in vivo against T cell lymphoma: Implication of modulated apoptosis, reactive oxygen species homeostasis, glucose metabolism, and pH regulation

Blockade of phosphodiesterase 5 by sildenafil reduces tumor growth and potentiates tumor‐killing ability of cisplatin in vivo against T cell lymphoma: Implication of modulated apoptosis, reactive oxygen species homeostasis, glucose metabolism, and pH regulation

Greenhouse test of spraying dsRNA to control the western flower thrips, Frankliniella occidentalis, infesting hot peppers

Alkaliptosis induction counteracts paclitaxel‐resistant ovarian cancer cells via ATP6V0D1‐mediated ABCB1 inhibition

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