Malignant pleural mesothelioma (MPM) is an aggressive
cancer of the pleural surface and is associated with previous
asbestos exposure. The
chemotherapy drug is one of the main treatments, but the median survival ranges from 8 to 14 months from diagnosis. The redox homeostasis of
tumor cells should be carefully considered since elevated levels of ROS favor
cancer cell progression (proliferation and migration), while a further elevation leads to ferroptosis. This study aims to analyze the functioning/role of
aquaporins (AQPs) as a
hydrogen peroxide (H2O2) channel in epithelial and biphasic MPM cell lines, as well as their possible involvement in
chemotherapy drug resistance. Results show that AQP-3, -5, -6, -9, and -11 were expressed at
mRNA and
protein levels. AQP-6 was localized in the plasma membrane and intracellular structures. Compared to normal mesothelial cells, the water permeability of
mesothelioma cells is not reduced by exogenous oxidative stress, but it is considerably increased by heat stress, making these cells resistant to ferroptosis. Functional experiments performed in
mesothelioma cells silenced for
aquaporin-6 revealed that it is responsible, at least in part, for the increase in H2O2 efflux caused by heat stress. Moreover,
mesothelioma cells knocked down for AQP-6 showed a reduced proliferation compared to mock cells. Current findings suggest the major role of AQP-6 in providing
mesothelioma cells with the ability to resist oxidative stress that underlies their resistance to
chemotherapy drugs.