Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability
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nihms828767.pdf
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Author(s)
Pattabiraman, D. R.
Bierie, B.
Kober, K. I.
Thiru, P.
Krall, J. A.
Zill, C.
Reinhardt, F.
Tam, W. L.
Date Issued
January 2016
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Pattabiraman, D. R. et al. “Activation of PKA Leads to Mesenchymal-to-Epithelial Transition and Loss of Tumor-Initiating Ability.” Science 351, 6277 (March 2016): aad3680 © 2016 American Association for the Advancement of Science
Version
Author's final manuscript
Abstract
The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology)
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/SCIENCE.AAD3680
