ZnT2-overexpression represses the cytotoxic effects of zinc hyper-accumulation in malignant metallothionein-null T47D breast tumor cells

摘要: Abstract Human breast tumors accumulate abnormally high levels of zinc (Zn). As a result, numerous studies have implicated Zn hyper-accumulation in the etiology cancer. Zinc accumulation can be cytotoxic, therefore cells Zn-buffering mechanisms, such as metallothioneins (MT) and vesicular sequestration, which tightly regulate homeostasis. The transporter ZnT2 sequesters into intracellular vesicles thus protect from cytotoxicity. Herein, we report that malignant tumor (T47D) do not express MT but ∼4-fold greater compared with non-malignant (MCF-10A) cells. coincided over-expression increased pools. In this study, hypothesized suppression would eliminate protection result cytotoxicity Suppression significantly cytoplasmic pools (1.6-fold) assessed Zn-responsive reporter assay containing four metal response elements (4X-MRE) fused to luciferase. Increased activated apoptosis caspase-independent manner. We observed significant generation reactive oxygen species (ROS) (2.3-fold), lysosomal swelling cathepsin D leakage ZnT2-attenuated ZnT2-expressing Most importantly, cell viability formation were decreased (∼25%) Our data indicate protects MT-null by sequestering vesicles. Moreover, our results implicate compartmentalizing mechanisms novel targets for cancer therapy.