Malignant pleural mesothelioma patients who have high levels of the signaling factor AKT1 have a worse prognosis, researchers reported in the journal Oncotarget. Blocking the signaling pathway, however, boosts the expression of the tumor suppressor ERβ – an approach that could be used to develop new mesothelioma treatments.
Researchers have known for some time that the AKT1 signaling pathway is involved in both mesothelioma progression and its resistance to chemotherapy.
Each of the three different AKTs have somewhat different roles, and the research team from the University of Eastern Piedmont Amedeo Avogadro, Italy, has previously described that two of them – AKT1 and 3 – are present in mesothelioma cells derived from patients.
In their new study, “SIRT1 at the crossroads of AKT1 and ERβ in malignant pleural mesothelioma cells,” the researchers further looked into the role of these molecules in patients, noting that only AKT1 levels could predict survival — which was shorter in patients with higher levels of the factor.
When studying the cells in the lab, the team noted that the AKT1 factor was important for the growth of tumor cells without attachment to a surface, a typical feature of certain cancers. This led them to further explore other proteins involved in this effect.
Among a row of identified molecules, the researchers noted a molecular trio interacting to produce the tumor-promoting effects. AKT1 increased the levels of the protein SIRT1, which in turn activated the transcription factor FOXM1 — able to alter the expression of genes.
One of the genes under the influence of FOXM1 turned out to be the tumor suppressor ERβ, downplayed by the molecular actions of the signaling pathway. When the researchers blocked AKT1, or SIRT1 signaling, ERβ levels increased. Since ERβ can act in the other direction via a feedback loop blocking SIRT1, preventing either AKT1 or SIRT1 from functioning, it can release the brake on the pathway.
Using this knowledge, the research team treated the cells with an activator of ERβ and noted that by blocking SIRT1, the function of AKT1 was also affected, and the molecule was no longer able to signal via its usual path.
The authors concluded that the findings may provide a number of targets for drug development focused on new approaches for treating mesothelioma.