Epigenetic silencing of Na,K-ATPase β<sub>1</sub>subunit gene<i>ATP1B1</i>by methylation in clear cell renal cell carcinoma

Selvakumar, Ponniah; Owens, Tori A.; David, Justin M.; Petrelli, Nicholas J.; Christensen, Brock C.; Lakshmikuttyamma, Ashakumary; Rajasekaran, Ayyappan K.

doi:10.4161/epi.27795

Cited by 33 publications

(31 citation statements)

References 42 publications

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“…This led us to reveal that Na + /K + -ATPase protects against the cytotoxicity and that ouabain, a Na + /K + -ATPase inhibitor, can enhance it. Reduced Na + /K + -ATPase activity has been observed in human renal cell carcinomas associated with reduced β 1 -subunit (10, 11). Therefore, if (−)-EA is pursued as a therapeutic direction, it might be worthwhile to monitor Na + /K + -ATPase as an indicator of potential (−)-EA sensitivity.…”

Section: Discussionmentioning

confidence: 99%

(−)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase

Ludlow

Gaunt

Rubaiy

et al. 2017

Journal of Biological Chemistry

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(−)-Englerin A ((−)-EA) has a rapid and potent cytotoxic effect on several types of cancer cell that is mediated by plasma membrane ion channels containing transient receptor potential canonical 4 (TRPC4) protein. Because these channels are Ca2+-permeable, it was initially thought that the cytotoxicity arose as a consequence of Ca2+ overload. Here we show that this is not the case and that the effect of (−)-EA is mediated by a heteromer of TRPC4 and TRPC1 proteins. Both TRPC4 and TRPC1 were required for (−)-EA cytotoxicity; however, although TRPC4 was necessary for the (−)-EA-evoked Ca2+ elevation, TRPC1 was not. TRPC1 either had no role or was a negative regulator of Ca2+ entry. By contrast, both TRPC4 and TRPC1 were necessary for monovalent cation entry evoked by (−)-EA, and (−)-EA-evoked cell death was dependent upon entry of the monovalent cation Na+. We therefore hypothesized that Na+/K+-ATPase might act protectively by counteracting the Na+ load resulting from sustained Na+ entry. Indeed, inhibition of Na+/K+-ATPase by ouabain potently and strongly increased (−)-EA-evoked cytotoxicity. The data suggest that (−)-EA achieves cancer cell cytotoxicity by inducing sustained Na+ entry through heteromeric TRPC1/TRPC4 channels and that the cytotoxic effect of (−)-EA can be potentiated by Na+/K+-ATPase inhibition.

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Section: Discussionmentioning

confidence: 99%

(−)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase

Ludlow

Gaunt

Rubaiy

et al. 2017

Journal of Biological Chemistry

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“…The regulation of the β ‐subunit is crucial not only for the regulation of the Na + /K + ‐ATPase, but also for the role it plays in cancer suppression through cancer metastasis and tumorigenesis, which is now being increasingly understood. It has been found that epigenetic regulation, in which methylation of the ATP1B1 downregulates expression of the β ‐subunit, promotes the growth of renal cell carcinoma . Cardiac glycosides have been shown to exhibit an antiproliferative effect on cancer cells due to their inhibitory effect on the Na + /K + ‐ATPase …”

Section: Molecular Targets Of Caridiac Glycosides As Anticancer Agentsmentioning

confidence: 99%

“…Epithelial‐to‐mesenchymal transition is a process that allows epithelial cells to change their phenotype, acquire mesenchymal properties, and increase their capability to migrate; it is a key process in cancer development and invasion because of its ability to spread throughout the body . The β ‐subunit of the sodium‐potassium pump has been shown to help regulate the integrity of epithelial polarization for a given cell . The β ‐subunit of the sodium‐potassium pump dimerizes to a neighbouring β ‐subunit to enhance the cell‐to‐cell adhesion through β ‐ β bridges.…”

Section: Molecular Targets Of Caridiac Glycosides As Anticancer Agentsmentioning

confidence: 99%

“…It has been found that epigenetic regulation, in which methylation of the ATP1B1 downregulates expression of the bsubunit, promotes the growth of renal cell carcinoma. 19 Cardiac glycosides have been shown to exhibit an antiproliferative effect on cancer cells due to their inhibitory effect on the Na + /K + -AT-Pase. 20…”

Section: Molecular Targets Of Caridiac Glycosides As Anticancer Agentsmentioning

confidence: 99%

“…21 The b-subunit of the sodiumpotassium pump has been shown to help regulate the integrity of epithelial polarization for a given cell. 19 The b-subunit of the sodium-potassium pump dimerizes to a neighbouring b-subunit to enhance the cell-to-cell adhesion through b-b bridges. As the expression of the b-subunit decreases, the protein expression of E-cadherin also decreases.…”

Section: Effects On Emtmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Na⁺/K⁺‐translocating adenosine triphosphatase in cancer treatment

Durlacher

Chow

Chen

et al. 2015

Clin Exp Pharma Physio

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Summary The Na+/K+‐translocating adenosine triphosphatase (ATPase) transports sodium and potassium across the plasma membrane and represents a potential target in cancer chemotherapy. Na+/K+‐ATPase belongs to the P‐type ATPase family (also known as E1–E2 ATPase), which is involved in transporting certain ions, metals, and lipids across the plasma membrane of mammalian cells. In humans, the Na+/K+‐ATPase is a binary complex of an α‐subunit that has four isoforms (α1–α4) and a β‐subunit that has three isoforms (β1–β3). This review aims to update our knowledge on the role of Na+/K+‐ATPase in cancer development and metastasis, as well as on how Na+/K+‐ATPase inhibitors kill tumour cells. The Na+/K+‐ATPase has been found to be associated with cancer initiation, growth, development, and metastasis. Cardiac glycosides have exhibited anticancer effects in cell‐based and mouse studies via inhibition of the Na+/K+‐ATPase and other mechanisms. Na+/K+‐ATPase inhibitors may kill cancer cells via induction of apoptosis and autophagy, radical oxygen species production, and cell cycle arrest. They also modulate multiple signalling pathways that regulate cancer cell survival and death, which contributes to their antiproliferative activities in cancer cells. The clinical evidence supporting the use of Na+/K+‐ATPase inhibitors as anticancer drugs is weak. Several phase I and phase II clinical trials with digoxin, Anvirzel, and huachansu (an intravenous formulated extract of the venom of the wild toad), either alone or more often in combination with other anticancer agents, have shown acceptable safety profiles but limited efficacy in cancer patients. Well‐designed randomized clinical trials with reasonable sample sizes are certainly warranted to confirm the efficacy and safety of cardiac glycosides for the treatment of cancer.

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Electrolyte Secretion and Absorption in the Small Intestine and Colon

Barrett

Keely

2015

Yamada' S Textbook of Gastroenterology

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Epigenetic silencing of Na,K-ATPase β₁subunit geneATP1B1by methylation in clear cell renal cell carcinoma

Cited by 33 publications

References 42 publications

(−)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase

(−)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase

Targeting Na⁺/K⁺‐translocating adenosine triphosphatase in cancer treatment

Electrolyte Secretion and Absorption in the Small Intestine and Colon

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Epigenetic silencing of Na,K-ATPase β1subunit geneATP1B1by methylation in clear cell renal cell carcinoma

Cited by 33 publications

References 42 publications

(−)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase

(−)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase

Targeting Na+/K+‐translocating adenosine triphosphatase in cancer treatment

Electrolyte Secretion and Absorption in the Small Intestine and Colon

Contact Info

Product

Resources

About

Epigenetic silencing of Na,K-ATPase β₁subunit geneATP1B1by methylation in clear cell renal cell carcinoma

Targeting Na⁺/K⁺‐translocating adenosine triphosphatase in cancer treatment