Modulation of MEK/ERK and mTOR pathways by Na + ‐K + ‐ATPase and AMPK inhibitors in ovarian cancer cells

Abstract only In addition to ion transport activities, Na + ‐K + ‐ATPase acts as a cellular signal transduction molecule. Its inhibitors, such as Ouabain, induce the EGFR/ERK pathway as well as the PI3K/AKT pathway. AMPK is involved in cellular metabolism and inhibiting the mTOR pathway. Activation...

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Bibliographic Details
Published in:The FASEB journal Vol. 31; no. S1
Main Authors: Clark, Matthew P, Madigan, Audrey, Gallant, Benjamin Paul, Zhang, Wei, Lu, Hongguang, Wan, Yinsheng
Format: Journal Article
Language:English
Published: 01-04-2017
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Summary:Abstract only In addition to ion transport activities, Na + ‐K + ‐ATPase acts as a cellular signal transduction molecule. Its inhibitors, such as Ouabain, induce the EGFR/ERK pathway as well as the PI3K/AKT pathway. AMPK is involved in cellular metabolism and inhibiting the mTOR pathway. Activation of AMPK leads to cell growth inhibition and apoptosis in cancer cells. Reports have demonstrated that activation of the AMPK stimulates Na + ‐K + ‐ATPase. In this study, we investigated the effects of both the Na + ‐K + ‐ATPase inhibitor Ouabain and the AMPK inhibitor Compound C on ovarian cancer cells. MTT assay results showed that both Ouabain and Compound C alone decrease cell viability. The combination of both yields a synergistic effect. Western blot analysis results indicated that Ouabain induces AKT/mTOR and ERK activation in a time and dose dependent manner. Interestingly, while Compound C inhibits Ouabain‐induced mTOR activation as measured by S6 phosphorylation in a dose dependent manner, Compound C enhances Ouabain‐induced ERK activation. Compound C alone induces ERK activation. Further studies showed that the MEK/ERK inhibitor U0126, but not the mTOR inhibitor Rapamycin, inhibits Ouabain‐induced S6 phosphorylation. ER redox assay data showed that Compound C treatment alters the redox level. Mito‐Tracker test data showed that both Ouabain and compound C increase mitochondria activities. Taken together, our data indicates that both Na + ‐K + ‐ATPase and AMPK are important for MEK/ERK and mTOR pathways in ovarian cancer cells. Modulation by inhibitors of both may reveal molecular targets for cancer treatments. Support or Funding Information RI‐INBRE
ISSN:0892-6638
1530-6860
DOI:10.1096/fasebj.31.1_supplement.614.18