Targeting the Lysosome for Cancer Therapy

Abstract

<b/> Lysosomes are the recycling centers of the cell where organelles and proteins are degraded during autophagy and macropinocytosis; they also serve as signaling hubs that control the activity of mTORC1. In this issue, Rebecca and colleagues report the development of a new type of lysosomal inhibitor for cancer therapy that can inhibit multiple lysosomal activities that are needed for tumor cell survival and growth. Cancer Discov; 7(11); 1218-20. ©2017 AACRSee related article by Rebecca et al., p. 1266.

Figure 1. DQ661 inhibits PPT1 to regulate multiple lysosome-mediated cellular processes

(A) Under basal conditions in the absence of DQ661 the lysosome can fuse with both autophagosomes to mediate autophagic degradation and endosomes to recycle nutrients from the extracellular environment via macropinocytosis. Additionally, the lysosome is the site of mTORC1 mediated signaling, which can result in decreased autophagosome initiation. (B) DQ661 can bind directly to PPT1 in the lysosome inhibiting recruitment of vATPase subunits and mTORC1 to the lysosomal membrane and disrupting the Ragulator complex and Rheb mediated activation of mTORC1. This results in decreased protein synthesis, a build up of autophagosomes that cannot fuse with the lysosome thus blocking autophagic flux as well as a decrease in endosome fusion with lysosomes with a net decrease in proliferation, autophagic flux and macropinocytosis. Inhibition of these multiple lysosomal processes result an increase in apoptosis and decreased tumor growth.