Specific aquaporins facilitate Nox-produced hydrogen peroxide transport through plasma membrane in leukaemia cells

Abstract

In the last decade, the generation and the role of reactive oxygen species (ROS), particularly hydrogen peroxide, in cell signalling transduction pathways have been intensively studied, and it is now clear that an increase of ROS level affects cellular growth and proliferation pathways related to cancer development. Hydrogen peroxide (H2O2) has been long thought to permeate biological membranes by simple diffusion since recent evidence challenged this notion disclosing the role of aquaporin water channels (AQP) in mediating H2O2 transport across plasma membranes. We previously demonstrated that NAD(P)H oxidase (Nox)-generated ROS sustain glucose uptake and cellular proliferation in leukaemia cells. The aim of this study was to assess whether specific AQP isoforms can channel Nox-produced H2O2 across the plasma membrane of leukaemia cells affecting downstream pathways linked to cell proliferation. In this work, we demonstrate that AQP inhibition caused a decrease in intracellular ROS accumulation in leukaemia cells both when H2O2 was produced by Nox enzymes and when it was exogenously added. Furthermore, AQP8 overexpression or silencing resulted to modulate VEGF capacity of triggering an H2O2 intracellular level increase or decrease, respectively. Finally, we report that AQP8 is capable of increasing H2O2-induced phosphorylation of both PI3K and p38 MAPK and that AQP8 expression affected positively cell proliferation. Taken together, the results here reported indicate that AQP8 is able to modulate H2O2 transport through the plasma membrane affecting redox signalling linked to leukaemia cell proliferation.

Stress Regulates Aquaporin-8 Permeability to Impact Cell Growth and Survival

“…Recently, members of the aquaporin protein family (AQP), initially described as bidirectional water transporters (1), have been found to channel also H 2 O 2 (7). We have recently shown that aquaporin-8 (AQP8) is essential to allow effective transport of H 2 O 2 across the plasma membrane, thus potentiating tyrosine phosphorylation induced by growth factors (6), a notion later corroborated by others (57). These data confirmed that H 2 O 2 acts as a rheostat of tyrosine kinase signaling and demonstrated that AQP8 guarantees efficient cytosolic import of H 2 O 2 likely produced by NOXes.…”

Aquaporins facilitate hydrogen peroxide entry into guard cells to mediate ABA- and pathogen-triggered stomatal closure

“…This function was recently extended to NF-κB signaling in keratinocytes (32) or in response to environmental stresses in colonic epithelia (33). Similarly, AQP8 facilitates cellular accumulation of H 2 O 2 after VEGF stimulation, thereby enhancing PI3K activity and phosphorylation of MAPKs, two essential processes for leukemia cell proliferation (34). Combined with our previous work (11), the present study indicates that the contribution of AtPIP2;1 to guard cell responses to ABA and flg22 involves both a signaling and a hydraulic function.…”

Transit of H2O2 across the endoplasmic reticulum membrane is not sluggish

“…This topological problem is solved by membrane-embedded aquaporin channels (AQPs). By serving as H 2 O 2 pores they facilitate the formation of local areas with an elevated H 2 O 2 concentration on both sides of the plasma membrane [13][14][15][16].…”