Aquaporin-6 May Increase the Resistance to Oxidative Stress of Malignant Pleural Mesothelioma Cells

Abstract

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.

Unexpected Classes of Aquaporin Channels Detected by Transcriptomic Analysis in Human Brain Are Associated with Both Patient Age and Alzheimer’s Disease Status

“…We identified novel RNAseq signals for AQPs 0, 3, 5, 6, 7, 8, 10 and 11 in the human brain in hippocampal and cortical regions known to be impacted by Alzheimer’s disease. Of these channels, peroxiporins AQPs 0, 6 and 8 [ 21 , 23 , 24 ] (which are permeable to H2O2) and the aquaglyceroporin AQP10 (permeable to glycerol) were expressed at higher levels in AD as compared to young controls.…”

“…AQP5 shows peroxiporin activity in the eye (21). Three classes of AQPs that showed increased levels in brain regions only in the presence of Alzheimer’s disease (AQPs 0, 6, 8) also are known to function as peroxiporins [ 21 , 23 , 24 ]. AQP0 has been characterized as an intrinsic membrane protein uniquely expressed in the eye lens and has been shown to facilitate transmembrane fluxes of H 2 O 2 [ 21 , 64 ].…”

“…AQP0 expression in the brain is a novel finding. In the hippocampus, AQP6, which has been characterised as a peroxiporin in malignant pleural mesothelioma [ 23 ], also was higher in the AD cohort. AQP8, a pancreatic β-cell peroxiporin, similarly was detected at high levels in the TCx of AD patients.…”

“…For example, AQP0 and 5 have both been shown to be permeable to hydrogen peroxide (H 2 O 2 ) in addition to water [ 21 , 22 ], prompting an additional descriptor as ‘peroxiporins’. Similarly, AQPs 6, 8 and 11 are all classified as peroxiporins [ 23 , 24 , 25 ]. AQP subtypes initially characterized by their permeability to both glycerol and water are classified as aquaglyceroporins, including AQPs 3, 7, 9 and 10 [ 26 ], although AQP9 has also been shown to permeate H 2 O 2 in mice [ 27 ].…”

Critical Role of Aquaporins in Cancer: Focus on Hematological Malignancies

“…These AQPs have high hydrogen peroxide (H 2 O 2 ) permeability and has an effect in ROS scavenging. Some studies assessed a role of AQP6 in driving the H 2 O 2 efflux from malignant pleural mesothelioma cells, and this action could justify the resistance of this tumor to conventional chemotherapy and radiotherapy [ 44 ]. Furthermore, AQP3-mediated H 2 O 2 transport has been correlated to breast cancer cell migration, and AQP5 facilitating transmembrane H 2 O 2 diffusion is able to modulate cell proliferation of cancer yeast cells in response to oxidative stress.…”