Cathepsin D: A Novel Target for Apoptotic Induction, as a Future Anti-Cancer Therapy: a Review

Abstract

Among many chemotherapeutic targets, apoptosis is one of the major targets as it reduces the cell mass and thus also control cell proliferation. Apoptosis is strictly regulated through many molecular mechanisms, including the proteolytic enzymes such as cathepsin D. Cathepsin D, a lysosomal aspartyl endopeptidase, regulates intrinsic apoptotic pathway. Presence of cathepsin D in the cytosol activates caspase-8 which induces the apoptotic pathway. Cathepsin D also stimulates the apoptosis by DNA damaging agents and through p53 dependent non-mitochondrial apoptotic pathway. Cathepsin D being a lysosomal enzyme has to be released into cytosol by changing the lysosomal membrane potential or by the over expression of cathepsin d gene. Concanamycin A and Bafilomycin A1, specific inhibitor of V-type ATPase might change the lysosome membrane potential releasing cathepsin D in the cytosol and inducing apoptosis. Lysosome membrane can also be ruptured by generation of intracellular reactive oxygen species (ROS). The over expression cathepsin D can be initiated by the hormonal treatment like estradiol and retinoic acid as the gene is regulated by mixed promoter. Over expression leads to accumulation of cathepsin D in the cytosol might induce apoptosis.