Engaging the Lysosome and Lysosome-Dependent Cell Death in Cancer

While patient-specific targeting of cellular growth and viability pathways dominates current approaches in anti cancer therapeutics development, appreciation for the strategy of targeting transformation-dependent alterations in cellular organelle structure and function continues to grow. Here we discuss the lysosome as an anti-cancer target, highlighting its role as a key mediator of cell death. As the major degradative compartment of the cell, the lysosome houses dozens of destructive enzymes and is responsible for the breakdown of both internal and external molecules and particles; however, until relatively recently the contribution of the lysosome to cellular death mechanisms has been largely overlooked. Renewed interest in the therapeutic potential of lysosomal rupture to combat cancer has led to development of lysosome-disrupting agents that induce lysosomal membrane permeabilization (LMP), cathepsin protease release, and subsequent lysosome dependent cell death (LDCD), now distinguished as a bona fide cell death process. Here, we present the basic biology, structure, and function of the lysosome, with particular emphasis on the transformation-associated alterations that sensitize cancer cell lysosomes to membrane rupture. We further describe the lysosome's role in cell death and comprehensively outline emerging therapeutic strategies that exploit lysosomes for the treatment of a variety of malignancies.