SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells

Our plain-English summary of SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells, by G. Pinton, S. Zonca, A.G. Manente, et al (Oncotarget, 2016).

The study

• Authors: G. Pinton, S. Zonca, A.G. Manente, M. Cavaletto, E. Borroni, A. Daga, P.V. Jithesh, D. Fennell, S. Nilsson, L. Moro
• Journal: Oncotarget
• Published: 2016;7(12):14366-79
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study of malignant pleural mesothelioma. It did not study asbestos exposure. The authors first reanalysed a publicly available gene-expression data set covering 40 mesothelioma tumors. Patients whose tumors had high AKT1 gene-expression levels had a significantly worse probability of survival (p=0.05). AKT3 gene-expression levels showed no significant link with survival (p=0.75). In a mesothelioma cell line, reducing AKT1 made cells look more epithelioid and significantly reduced their ability to form colonies in soft agar. Reducing AKT3 did not significantly change colony numbers. A drug that blocks AKT activation (MK2206) did not change cell shape or colony formation. Reducing the protein SIRT1 increased acetylation of AKT1, lowered its activation, and raised levels of estrogen receptor beta (ERβ). In a second cell line, the ERβ-activating compound KB9520 lowered SIRT1 and FOXM1. In tumors grown in mice, KB9520 increased the association of acetylated AKT1 with three other proteins, compared with vehicle-treated control mice. The authors concluded the results may aid development of AKT-isoform-targeted mesothelioma treatment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: reanalysis of a public tumor gene-expression data set with survival data, experiments in mesothelioma cell lines, and a mouse tumor experiment
• Who was studied: Gene-expression and survival data for 40 malignant pleural mesothelioma patients from public data set GSE 2549. Two mesothelioma cell lines: biphasic MSTO-211H and epithelioid REN. Male CD1 nude mice injected in the peritoneum with MSTO-211H cells, in treatment groups of ten animals.
• Exposure: No asbestos exposure was studied. The experimental treatments were: silencing of AKT1, AKT3, SIRT1 or FOXM1; the AKT inhibitor MK2206 (8 nM); and the ERβ agonist KB9520 (10 nM in cells; 10 mg/kg/day in mice, days 15 to 40).
• Main results:
  • Among the 40 patients in the data set, high tumor AKT1 gene expression was associated with significantly worse survival (p=0.05). AKT3 gene expression showed no significant correlation with survival (p=0.75).
  • Neither AKT1 nor AKT3 expression levels were significantly associated with histologic subtype (p=0.4 and p=0.89).
  • In MSTO-211H cells, reducing AKT1 significantly reduced colony formation in soft agar. Reducing AKT3 did not.
  • Blocking AKT activation with MK2206 did not affect network formation on Matrigel or colony numbers in MSTO-211H cells.
  • In MSTO-211H cells, silencing SIRT1 increased AKT1 acetylation and inhibited its phosphorylation without changing AKT1 expression.
  • In MSTO-211H cells, eleven proteins were identified that were co-immunoprecipitated with acetylated AKT after SIRT1 silencing.
  • In MSTO-211H cells, SIRT1 silencing increased ERβ expression.
  • In REN cells, KB9520 decreased SIRT1 and FOXM1 expression and shifted AKT1 from phosphorylated to acetylated form.
  • In MSTO-211H tumors from mice treated with KB9520, acetylated AKT1 showed increased association with PARP1, HSC70 and GADPH, compared with tumors from vehicle-treated control mice.
• The authors' conclusion: The authors concluded that the results may aid development of strategies targeting specific AKT isoforms in mesothelioma therapy.
• Limitations the authors state:
  • The authors state that the mechanisms behind the different roles of AKT1 and AKT3, and why the effects did not depend on AKT1 activation, are not known.
  • The authors state that the role and location within the cell of acetylated AKT1, when in complexes with these proteins, need further study.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis.

Related studies

• PARP1 inhibition affects pleural mesothelioma cell viability and uncouples AKT/mTOR axis via SIRT1 — G. Pinton, A.G. Manente, et al. (2013)
• Intracellular lactate-mediated induction of estrogen receptor beta (ERβ) in biphasic malignant pleural mesothelioma cells — A.G. Manente, G. Pinton, et al. (2015)
• Agonist activation of estrogen receptor beta (ERβ) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity — G. Pinton, A.G. Manente, et al. (2014)
• KDM6B histone demethylase is an epigenetic regulator of estrogen receptor β expression in human pleural mesothelioma — A.G. Manente, G. Pinton, et al. (2016)
• Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1 — K.E. Hwang, Y.S. Kim, et al. (2015)
• Estrogen receptor β exerts tumor repressive functions in human malignant pleural mesothelioma via EGFR inactivation and affects response to gefitinib — G. Pinton, W. Thomas, et al. (2010)

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