Abstract
In this report, we show that malignant pleural mesothelioma (MPM) patients whose tumors express high levels of AKT1 exhibit a significantly worse prognosis, whereas no significant correlation with AKT3 expression is observed. We provide data that establish a phosphorylation independent role of AKT1 in affecting MPM cell shape and anchorage independent cell growth in vitro and highlight the AKT1 isoform-specific nature of these effects.We describe that AKT1 activity is inhibited by the loss of SIRT1-mediated deacetylation and identify, by mass spectrometry, 11 unique proteins that interact with acetylated AKT1.Our data demonstrate a role of the AKT1/SIRT1/FOXM1 axis in the expression of the tumor suppressor ERβ. We further demonstrate an inhibitory feedback loop by ERβ, activated by the selective agonist KB9520, on this axis both in vitro and in vivo.Our data broaden the current knowledge of ERβ and AKT isoform-specific functions that could be valuable in the design of novel and effective therapeutic strategies for MPM.
Highlights
Human malignant pleural mesothelioma (MPM) is an aggressive cancer, closely linked to asbestos exposure, with very poor survival rates [1, 2]
We describe that AKT1 activity is inhibited by the loss of SIRT1-mediated deacetylation and identify, by mass spectrometry, 11 unique proteins that interact with acetylated AKT1
We recently described that AKT1 is involved in the regulation of ERβ expression, a tumor suppressor and positive prognostic factor in patients diagnosed with MPM [29]
Summary
Human malignant pleural mesothelioma (MPM) is an aggressive cancer, closely linked to asbestos exposure, with very poor survival rates [1, 2]. In the second line setting, various chemotherapy agents are used, either as monotherapy or as part of polytherapy, but none has been validated and no approved drugs reverse disease progression [6, 7]. The PI3K/AKT signaling pathway is aberrantly active and has an important biologic impact in MPM progression and chemo-resistance [8, 9]. AKT serinethreonine kinases function as critical regulators of tumor cell survival, proliferation, metabolism and migration. Enhanced AKT activity confers resistance to endocrine and molecular-targeted therapeutics including cytotoxic and genotoxic drugs. There may be isoform-specific functions in tumor cells due to amplifications and mutations of upstream components of the PI3K/AKT signaling pathway [12]. Reversible acetylation of lysine residues, by histone acetyltransferases (HATs) and histone deacetylases (HDACs), was recently described as a post-translational regulatory mechanism that controls the activity of AKT [17]
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