Abstract
Microtubule-disturbing drugs inhibit lysosomal trafficking and induce lysosomal membrane permeabilization followed by cathepsin-dependent cell death. To identify specific trafficking-related proteins that control cell survival and lysosomal stability, we screened a molecular motor siRNA library in human MCF7 breast cancer cells. SiRNAs targeting four kinesins (KIF11/Eg5, KIF20A, KIF21A, KIF25), myosin 1G (MYO1G), myosin heavy chain 1 (MYH1) and tropomyosin 2 (TPM2) were identified as effective inducers of non-apoptotic cell death. The cell death induced by KIF11, KIF21A, KIF25, MYH1 or TPM2 siRNAs was preceded by lysosomal membrane permeabilization, and all identified siRNAs induced several changes in the endo-lysosomal compartment, i.e. increased lysosomal volume (KIF11, KIF20A, KIF25, MYO1G, MYH1), increased cysteine cathepsin activity (KIF20A, KIF25), altered lysosomal localization (KIF25, MYH1, TPM2), increased dextran accumulation (KIF20A), or reduced autophagic flux (MYO1G, MYH1). Importantly, all seven siRNAs also killed human cervix cancer (HeLa) and osteosarcoma (U-2-OS) cells and sensitized cancer cells to other lysosome-destabilizing treatments, i.e. photo-oxidation, siramesine, etoposide or cisplatin. Similarly to KIF11 siRNA, the KIF11 inhibitor monastrol induced lysosomal membrane permeabilization and sensitized several cancer cell lines to siramesine. While KIF11 inhibitors are under clinical development as mitotic blockers, our data reveal a new function for KIF11 in controlling lysosomal stability and introduce six other molecular motors as putative cancer drug targets.
Highlights
Lysosomes are acidic vesicles containing numerous hydrolases, which degrade organelles and macromolecules delivered to them by autophagy, endocytosis and phagocytosis [1]
We identified KIF11, KIF20A, KIF21, KIF25, myosin 1G (MYO1G), myosin heavy chain 1 (MYH1) and tropomyosin 2 (TPM2) as proteins whose depletion causes growth inhibition and non-apoptotic cell death in cancer cells (Table 1)
To the findings in our previous study showing that the depletion of KIF5B is more toxic to HeLa cells than to MCF7 cells [31], we observed some differences in the sensitivities of the different cancer cell lines to the identified siRNAs
Summary
Lysosomes are acidic vesicles containing numerous hydrolases, which degrade organelles and macromolecules delivered to them by autophagy, endocytosis and phagocytosis [1]. Among the cancer drugs that activate lysosomal cell death are microtubule-destabilizing and -stabilizing drugs (e.g. vinca alkaloids and taxanes), which inhibit lysosomal trafficking and induce an expansion of the lysosomal compartment followed by lysosomal rupture and cathepsin-dependent cell death [7,8]. Such a severe cytoskeletal disturbance affects vital processes in healthy cells leading to toxicity in patients [9]. A more specific targeting of lysosomal trafficking might improve therapy considerably
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