Dual targeting of tumor cell energy metabolism and lysosomes as an anticancer strategy.

To sustain their proliferative and metastatic capacity, tumor cells increase the activity of energy-producing pathways and lysosomal compartment, resorting to autophagolysosomal degradation when nutrients are scarce. Consequently, large fragile lysosomes and enhanced energy metabolism may serve as targets for anticancer therapy. A simultaneous induction of energy stress (by caloric restriction and inhibition of glycolysis, oxidative phosphorylation, Krebs cycle, or amino acid/fatty acid metabolism) and lysosomal stress (by lysosomotropic detergents, vacuolar ATPase inhibitors, or cationic amphiphilic drugs) is an efficient anti-cancer strategy demonstrated in a number of studies. However, the mechanisms of lysosomal/energy stress co-amplification, apart from the protective autophagy inhibition, are poorly understood. We here summarize the established and suggest potential mechanisms and candidates for anticancer therapy based on the dual targeting of lysosomes and energy metabolism.