Na+/K+ ATPase activity promotes invasion of endocrine resistant breast cancer cells

Khajah, Maitham A.; Mathew, Princy M.; Luqmani, Yunus A.

doi:10.1371/journal.pone.0193779

Cited by 46 publications

(40 citation statements)

References 53 publications

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“…In esophageal squamous cell carcinoma, overexpression of Na+/K+ ATPase is associated with severity of the disease and is also reported in medulloblastoma, glioblastoma, melanoma, hepatomas, and non-small-cell lung cancer [79], and in breast cancer, it is reported to increase invasion of endocrine resistant cancer cells [80]. Although Qubain causes Na+/K+ATPase to interact with Src and EGFR, and can actıvate ERK1/2, it also results in growth arrest in human breast cancer cells, possibly by increasing the expression of p53 and p21 [81].…”

Section: Plos Onementioning

confidence: 92%

A novel 20-gene prognostic score in pancreatic adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Known risk factors for this disease are currently insufficient in predicting mortality. In order to better prognosticate patients with PDAC, we identified 20 genes by utilizing publically available high-throughput transcriptomic data from GEO, TCGA and ICGC which are associated with overall survival and event-free survival. A score generated based on the expression matrix of these genes was validated in two independent cohorts. We find that this "Pancreatic cancer prognostic score 20-PPS20" is independent of the confounding factors in multivariate analyses, is dramatically elevated in metastatic tissue compared to primary tumor, and is higher in primary tumors compared to normal pancreatic tissue. Transcriptomic analyses show that tumors with low PPS20 have overall more immune cell infiltration and a higher CD8 T cell/Treg ratio when compared to those with high PPS20. Analyses of proteomic data from TCGA PAAD indicated higher levels of Cyclin B1, RAD51, EGFR and a lower E-cadherin/Fibronectin ratio in tumors with high PPS20. The PPS20 score defines not only prognostic and biological subgroups but can predict response to targeted therapy as well. Overall, PPS20 is a stronger and more robust transcriptomic signature when compared to similar, previously published gene lists.

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Section: Plos Onementioning

confidence: 92%

A novel 20-gene prognostic score in pancreatic adenocarcinoma

et al. 2020

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“…Digoxin; Ouabain; 3,4,5,6-tetrahydroxyxanthone [153][154][155] Potassium-dependent sodium-calcium exchanger -…”

Section: The Name Of Proteins Modulatorsmentioning

confidence: 99%

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Alfarouk¹,

Ahmed

et al. 2020

Cancers

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Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism.

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“…The NKA complex is sensitive to reactive oxygen radicals (6)(7)(8)(9)(10)(11). We therefore reasoned that the inhibition of NKA activity was a downstream effect of plumbagin, occurring due to the damage of this ion transport complex by the intracellular oxygen radical flux.…”

Section: Nka Inhibitory Activity Is Abrogated By Oxygen Radical Scavementioning

confidence: 99%

“…Therefore, there are initiatives to develop NKA inhibitors as chemotherapeutics for the treatment of cancer. A majority of these studies have focused on digoxin, ouabain and other cardiac glycosides because of their known ability to potently inhibit NKA activity [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Plumbagin-induced oxidative stress leads to inhibition of Na⁺/K⁺-ATPase (NKA) in canine cancer cells

Alharbi

Kapur²,

Felder

et al. 2019

Preprint

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The Na + /K + -ATPase (NKA) complex is the master regulator of membrane potential and a target for anti-cancer therapies. Here, we investigate the effect of drug-induced oxidative stress on NKA activity. The natural product, plumbagin increases oxygen radicals through inhibition of oxidative phosphorylation. As a result, plumbagin treatment results in decreased production of ATP and a rapid increase in intracellular oxygen radicals. We show that plumbagin induces apoptosis in canine cancer cells via oxidative stress. We use this model to test the effect of oxidative stress on NKA activity. Using whole-cell patch-clamp electrophysiology we demonstrate that short-term exposure (4 min) to plumbagin results in 48% decrease in outward current at +50 mV. Even when exogenous ATP was supplied to the cells, plumbagin treatment resulted in 46% inhibition outward current through NKA at +50 mV. In contrast, when the canine cancer cells were pre-treated with the oxygen radical scavenger, N-acetylcysteine, the NKA inhibitory activity of plumbagin was abrogated. These experiments demonstrate that the oxidative stress-causing agents such as plumbagin and its analogues, are a novel avenue to regulate NKA activity in tumors. KeywordsPlumbagin, Na + /K + -ATPase, oxidative stress, electrophysiology, and canine cancer.

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Na+/K+ ATPase activity promotes invasion of endocrine resistant breast cancer cells

Cited by 46 publications

References 53 publications

A novel 20-gene prognostic score in pancreatic adenocarcinoma

A novel 20-gene prognostic score in pancreatic adenocarcinoma

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Plumbagin-induced oxidative stress leads to inhibition of Na⁺/K⁺-ATPase (NKA) in canine cancer cells

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Na+/K+ ATPase activity promotes invasion of endocrine resistant breast cancer cells

Cited by 46 publications

References 53 publications

A novel 20-gene prognostic score in pancreatic adenocarcinoma

A novel 20-gene prognostic score in pancreatic adenocarcinoma

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells

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Plumbagin-induced oxidative stress leads to inhibition of Na⁺/K⁺-ATPase (NKA) in canine cancer cells