Sulforaphane Modulates AQP8‐Linked Redox Signalling in Leukemia Cells

Abstract

Sulforaphane, a biologically active isothiocyanate compound extracted from cruciferous vegetables, has been shown to exert cytotoxic effects on many human cancer cells, including leukemia. However, the exact molecular mechanisms behind the action of sulforaphane in hematological malignancies are still unclear. Like other cancer cells, leukemia cells produce high level of reactive oxygen species; in particular, hydrogen peroxide derived from Nox family is involved in various redox signal transduction pathways, promoting cell proliferation and survival. Recent evidence show that many tumour cell types express elevated level of aquaporin isoforms, and we previously demonstrated that aquaporin-8 acts as H2O2 transport facilitator across the plasma membrane of B1647 cells, a model of acute myeloid human leukemia. Thus, the control of AQP8-mediated H2O2 transport could be a novel strategy to regulate cell signalling and survival. To this purpose, we evaluated whether sulforaphane could somehow affect aquaporin-8-mediated H2O2 transport and/or Nox-mediated H2O2 production in B1647 cell line. Results indicated that sulforaphane inhibited both aquaporin-8 and Nox2 expression, thus decreasing B1647 cells viability. Moreover, the data obtained by coimmunoprecipitation technique demonstrated that these two proteins are linked to each other; thus, sulforaphane has an important role in modulating the downstream events triggered by the axis Nox2-aquaporin-8. Cell treatment with sulforaphane also reduced the expression of peroxiredoxin-1, which is increased in almost all acute myeloid leukemia subtypes. Interestingly, sulforaphane concentrations able to trigger these effects are achievable by dietary intake of cruciferous vegetables, confirming the importance of the beneficial effect of a diet rich in bioactive compounds.

Peroxiporins in Cancer

“…This finding indicates that AQP3 and EGFR form a signaling module that triggers Nox activation to generate the second messenger H 2 O 2 which is transported into cells by an AQP3-mediated channeling. An association between Nox2 and another peroxiporin, AQP8, was reported also by Prata and Colleagues, who described the existence of VEGF-activated Nox2-AQP8 axis in a leukemic cell line [72]. The evidence of the interaction between AQP isoforms and Nox2 supports the importance of these two partners in the redox signaling cascade.…”

“…Prata and colleagues investigated the potential effect of the isothiocyanate sulforaphane (SFN) on the modulation of AQP8 and Nox expression in a model of human acute leukemia [72], since it was stated that SFN is able to selectively exert cytotoxic effects in many cancer types or being even cytoprotective in normal cells [112]. The results show that SFN (at concentrations readily reachable through dietary intake, i.e., 10 μM) downregulates AQP8 and Nox2 expression, limiting both H 2 O 2 production and entry into the cells.…”

“…The results show that SFN (at concentrations readily reachable through dietary intake, i.e., 10 μM) downregulates AQP8 and Nox2 expression, limiting both H 2 O 2 production and entry into the cells. By using a co-immunoprecipitation technique, it was also demonstrated that Nox2 and AQP8 are linked to each other, thus, by decreasing the effect of this Nox2-AQP8 axis, SFN causes profound effects on the redox signaling, survival and proliferation of these leukemic cells [72].…”

The Glucosinolates, A Sulphur Glucoside Family of Mustard Phytochemicals With Diverse Biomedical Application

“…Leukemia [87,124,[175][176][177][178][179] Prostate cancer [91,95,[180][181][182] non-small cell lung cancer cells [107,183,184] Pancreatic cancer [165,[185][186][187] Breast cancer [92, 93, 101-103, 105, 108, 109, 188-195] Bladder cancer [169,[196][197][198][199][200][201] Ovarian cancer [99] HepG2 Carcinoma Cells [202][203][204][205][206] Gastric cancer [207,208] Squamous cell carcinoma [209,210] Nasopharangeal cancer [211] Melanoma [212] Glioma [173,[213][214][215] Colon cancer [110,216,217] Lung cancer [218,219]...…”

Human Aquaporin-5 Facilitates Hydrogen Peroxide Permeation Affecting Adaption to Oxidative Stress and Cancer Cell Migration

“…Among these AQPs, some isoforms have also been shown to permeate ammonia [1,2]. More recently, a fourth sub-group comprising isoforms that facilitate the diffusion of H 2 O 2 through cell membranes has been identified and named peroxiporins [3,4,5,6,7].…”