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Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance.

Zhitomirsky B, Assaraf YG - Oncotarget (2015)

Bottom Line: Non-cytotoxic, nanomolar concentrations, of the hydrophobic weak base chemotherapeutics doxorubicin and mitoxantrone triggered rapid lysosomal biogenesis that was associated with nuclear translocation of TFEB, the dominant transcription factor regulating lysosomal biogenesis.This resulted in increased lysosomal gene expression and lysosomal enzyme activity.The current study provides the first evidence that drug-induced TFEB-associated lysosomal biogenesis is an emerging determinant of MDR and suggests that circumvention of lysosomal drug sequestration is a novel strategy to overcome this chemoresistance.

View Article: PubMed Central - PubMed

Affiliation: The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.

ABSTRACT
Multidrug resistance (MDR) is a primary hindrance to curative cancer chemotherapy. In this respect, lysosomes were suggested to play a role in intrinsic MDR by sequestering protonated hydrophobic weak base chemotherapeutics away from their intracellular target sites. Here we show that intrinsic resistance to sunitinib, a hydrophobic weak base tyrosine kinase inhibitor known to accumulate in lysosomes, tightly correlates with the number of lysosomes accumulating high levels of sunitinib in multiple human carcinoma cells. Furthermore, exposure of cancer cells to hydrophobic weak base drugs leads to a marked increase in the number of lysosomes per cell. Non-cytotoxic, nanomolar concentrations, of the hydrophobic weak base chemotherapeutics doxorubicin and mitoxantrone triggered rapid lysosomal biogenesis that was associated with nuclear translocation of TFEB, the dominant transcription factor regulating lysosomal biogenesis. This resulted in increased lysosomal gene expression and lysosomal enzyme activity. Thus, treatment of cancer cells with hydrophobic weak base chemotherapeutics and their consequent sequestration in lysosomes triggers lysosomal biogenesis, thereby further enhancing lysosomal drug entrapment and MDR. The current study provides the first evidence that drug-induced TFEB-associated lysosomal biogenesis is an emerging determinant of MDR and suggests that circumvention of lysosomal drug sequestration is a novel strategy to overcome this chemoresistance.

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Related in: MedlinePlus

A schematic summary model for hydrophobic weak base drug-induced lysosome-mediated drug resistanceHydrophobic weak base drugs enter the lysosomes by simple diffusion; undergo protonation in the acidic lysosomal lumen, thereby becoming irreversibly sequestered in lysosomes and acidic intracellular vesicles such as late endosomes. In turn, lysosomal drug sequestration triggers TFEB-mediated lysosomal biogenesis, resulting in a significant increase in the number of lysosomes per cell. Increased lysosome number per cell enhances the efficiency of lysosomal drug sequestration, with lysosomes acting as a sink pulling hydrophobic weak base drugs away from their cellular target sites, thereby resulting in MDR.
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Figure 7: A schematic summary model for hydrophobic weak base drug-induced lysosome-mediated drug resistanceHydrophobic weak base drugs enter the lysosomes by simple diffusion; undergo protonation in the acidic lysosomal lumen, thereby becoming irreversibly sequestered in lysosomes and acidic intracellular vesicles such as late endosomes. In turn, lysosomal drug sequestration triggers TFEB-mediated lysosomal biogenesis, resulting in a significant increase in the number of lysosomes per cell. Increased lysosome number per cell enhances the efficiency of lysosomal drug sequestration, with lysosomes acting as a sink pulling hydrophobic weak base drugs away from their cellular target sites, thereby resulting in MDR.

Mentions: Based on our current findings we propose an integrative model for hydrophobic weak base drug-induced lysosome-dependent drug resistance (Fig. 7). Hydrophobic weak base drugs enter the lysosomes by simple diffusion, become irreversibly protonated in the highly acidic lysosomes or late endosomes, undergo dramatic accumulation and consequently become irreversibly sequestered therein. In turn, lysosomal drug entrapment triggers TFEB-mediated lysosomal biogenesis via dephosphorylation of TFEB and its translocation from the cytoplasm to the nucleus. In the nucleus, this transcriptional master regulator transactivates the expression of multiple genes in the CLEAR pathway, thereby leading to lysosomal biogenesis and consequently marked increase in lysosome number per cell. Increased lysosomal number per cell increases the efficiency of lysosomal drug sequestration, with lysosomes acting as a sink pulling hydrophobic weak base drugs away from their cellular target sites, hence rendering tumor cells MDR.


Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance.

Zhitomirsky B, Assaraf YG - Oncotarget (2015)

A schematic summary model for hydrophobic weak base drug-induced lysosome-mediated drug resistanceHydrophobic weak base drugs enter the lysosomes by simple diffusion; undergo protonation in the acidic lysosomal lumen, thereby becoming irreversibly sequestered in lysosomes and acidic intracellular vesicles such as late endosomes. In turn, lysosomal drug sequestration triggers TFEB-mediated lysosomal biogenesis, resulting in a significant increase in the number of lysosomes per cell. Increased lysosome number per cell enhances the efficiency of lysosomal drug sequestration, with lysosomes acting as a sink pulling hydrophobic weak base drugs away from their cellular target sites, thereby resulting in MDR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359223&req=5

Figure 7: A schematic summary model for hydrophobic weak base drug-induced lysosome-mediated drug resistanceHydrophobic weak base drugs enter the lysosomes by simple diffusion; undergo protonation in the acidic lysosomal lumen, thereby becoming irreversibly sequestered in lysosomes and acidic intracellular vesicles such as late endosomes. In turn, lysosomal drug sequestration triggers TFEB-mediated lysosomal biogenesis, resulting in a significant increase in the number of lysosomes per cell. Increased lysosome number per cell enhances the efficiency of lysosomal drug sequestration, with lysosomes acting as a sink pulling hydrophobic weak base drugs away from their cellular target sites, thereby resulting in MDR.
Mentions: Based on our current findings we propose an integrative model for hydrophobic weak base drug-induced lysosome-dependent drug resistance (Fig. 7). Hydrophobic weak base drugs enter the lysosomes by simple diffusion, become irreversibly protonated in the highly acidic lysosomes or late endosomes, undergo dramatic accumulation and consequently become irreversibly sequestered therein. In turn, lysosomal drug entrapment triggers TFEB-mediated lysosomal biogenesis via dephosphorylation of TFEB and its translocation from the cytoplasm to the nucleus. In the nucleus, this transcriptional master regulator transactivates the expression of multiple genes in the CLEAR pathway, thereby leading to lysosomal biogenesis and consequently marked increase in lysosome number per cell. Increased lysosomal number per cell increases the efficiency of lysosomal drug sequestration, with lysosomes acting as a sink pulling hydrophobic weak base drugs away from their cellular target sites, hence rendering tumor cells MDR.

Bottom Line: Non-cytotoxic, nanomolar concentrations, of the hydrophobic weak base chemotherapeutics doxorubicin and mitoxantrone triggered rapid lysosomal biogenesis that was associated with nuclear translocation of TFEB, the dominant transcription factor regulating lysosomal biogenesis.This resulted in increased lysosomal gene expression and lysosomal enzyme activity.The current study provides the first evidence that drug-induced TFEB-associated lysosomal biogenesis is an emerging determinant of MDR and suggests that circumvention of lysosomal drug sequestration is a novel strategy to overcome this chemoresistance.

View Article: PubMed Central - PubMed

Affiliation: The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.

ABSTRACT
Multidrug resistance (MDR) is a primary hindrance to curative cancer chemotherapy. In this respect, lysosomes were suggested to play a role in intrinsic MDR by sequestering protonated hydrophobic weak base chemotherapeutics away from their intracellular target sites. Here we show that intrinsic resistance to sunitinib, a hydrophobic weak base tyrosine kinase inhibitor known to accumulate in lysosomes, tightly correlates with the number of lysosomes accumulating high levels of sunitinib in multiple human carcinoma cells. Furthermore, exposure of cancer cells to hydrophobic weak base drugs leads to a marked increase in the number of lysosomes per cell. Non-cytotoxic, nanomolar concentrations, of the hydrophobic weak base chemotherapeutics doxorubicin and mitoxantrone triggered rapid lysosomal biogenesis that was associated with nuclear translocation of TFEB, the dominant transcription factor regulating lysosomal biogenesis. This resulted in increased lysosomal gene expression and lysosomal enzyme activity. Thus, treatment of cancer cells with hydrophobic weak base chemotherapeutics and their consequent sequestration in lysosomes triggers lysosomal biogenesis, thereby further enhancing lysosomal drug entrapment and MDR. The current study provides the first evidence that drug-induced TFEB-associated lysosomal biogenesis is an emerging determinant of MDR and suggests that circumvention of lysosomal drug sequestration is a novel strategy to overcome this chemoresistance.

Show MeSH
Related in: MedlinePlus