Sub‐cellular zinc distribution: a novel role for lysosomal‐mediated cell death in malignant breast tumor cells

Abstract

Numerous studies implicate abnormally high zinc (Zn) levels in the etiology of breast cancer. ZnT2 plays role in Zn sequestration, protecting cells from the cytotoxic effects of excess Zn. We previously determined that ZnT2 is over‐expressed in malignant breast tumor cells. Intriguingly, ZnT2‐attenuation resulted in caspase‐independent apoptosis. Emerging evidence suggests that lysosomal rupture releases catabolic enzymes and activates or potentiates apoptosis. Numerous cytotoxic conditions, such as reactive oxygen species (ROS) generation induce permeabilization of lysosomal membranes. Thus, the primary objective of this study was to determine if ZnT2‐attentuation was associated with lysosome‐mediated apoptosis in tumor cells. We determined that ZnT2‐attenuated cells had significantly higher cytoplasmic Zn level compared with ZnT2‐expressing cells. Curiously, ZnT2‐attenuation significantly increased ROS generation, suggesting that re‐distribution of Zn resulted in lysosomal swelling. Taken together, these results illustrated that ZnT2‐attenuation increased ROS potentially revealing lysosomal membrane instability as an apoptotic signal in malignant breast tumor cells. Our data provide novel insight suggesting that changes in the Zn microenvironment regulate lysosome‐mediated cell death. Supported by DOD‐BCRP to SLK.