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

ABSTRACT: 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 of 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.

SUBMITTER: Alharbi Y

PROVIDER: S-EPMC6685937 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Fishes are equipped to sense stressful stimuli and are able to respond to environmental stressor such as hypoxia with varying pattern of stress response. The functional attributes of brain to hypoxia stress in relation to ion transport and its interaction during immune challenge have not yet delineated in fish. We, therefore, explored the pattern of ion transporter functions and messenger RNA (mRNA) expression of ?1-subunit isoforms of Na+/K+-ATPase (NKA) in the brain segments, namely, prosencephalon (PC), mesencephalon (MC), and metencephalon (MeC) in an obligate air-breathing fish exposed either to hypoxia stress (30 minutes forced immersion in water) or challenged with zymosan treatment (25-200 ng g-1 for 24 hours) or both. Zymosan that produced nonspecific immune responses evoked differential regulation of NKA, H+/K+-ATPase (HKA), and [Formula: see text] (NNA) in the varied brain segments. On the contrary, hypoxia stress that demanded activation of NKA in PC and MeC showed a reversed NKA activity pattern in MeC of immune-challenged fish. A compromised HKA and NNA regulation during hypoxia stress was found in immune-challenged fish, indicating the role of these brain ion transporters to hypoxia stress and immune challenges. The differential mRNA expression of ?1-subunit isoforms of NKA, nka?1a, nka?1b, and nka?1c, in hypoxia-stressed brain showed a shift in its expression pattern during hypoxia stress-immune interaction in PC and MC. Evidence is thus presented for the first time that ion transporters such as HKA and NNA along with NKA act as functional brain markers which respond differentially to both hypoxia stress and immune challenges. Taken together, the data further provide evidence for a differential Na+, K+, H+, and [Formula: see text] ion signaling that exists in brain neuronal clusters during hypoxia stress-immune interaction as a result of modified regulations of NKA, HKA, and NNA transporter functions and nka?1 isoform regulation.

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

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Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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