STF-62247 accumulates in lysosomes and blocks late stages of autophagy to selectively target von Hippel-Lindau-inactivated cells
Autor: | Dominique Comeau, Nadia Bouhamdani, Kevin Cormier, Sandra Turcotte |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
von Hippel-Lindau Disease Pyridines Physiology urologic and male genital diseases Endocytosis Homeostatic Process 03 medical and health sciences Drug Delivery Systems 0302 clinical medicine Autophagy medicine Humans Carcinoma Renal Cell Dose-Response Relationship Drug Chemistry Cancer Cell Biology Von hippel lindau medicine.disease Kidney Neoplasms female genital diseases and pregnancy complications 3. Good health Cell biology Thiazoles Cytosol 030104 developmental biology 030220 oncology & carcinogenesis Lysosomes HeLa Cells |
Zdroj: | American Journal of Physiology-Cell Physiology. 316:C605-C620 |
ISSN: | 1522-1563 0363-6143 |
Popis: | Autophagy is a highly conserved, homeostatic process by which cytosolic components reach lysosomes for degradation. The roles played by different autophagic processes in cancer are complex and remain cancer type and stage dependent. Renal cell carcinoma (RCC) is the most common subtype of kidney cancer and is characterized by the inactivation of the von Hippel-Lindau (VHL) tumor suppressor. Our previous study identified a small compound, STF-62247, as an autophagy-modulating molecule causing selective cytotoxicity for VHL-inactivated cells. This present study investigates the effects of STF-62247 specifically on the macroautophagic flux to better characterize its mechanism of action in RCC. Our results clearly demonstrate that this compound is a potent blocker of late stages of autophagy. We show that inhibiting autophagy by CRISPR knockouts of autophagy-related genes rendered VHL-deficient cells insensitive to STF-62247, uncovering the importance of the autophagic pathway in STF-selective cell death. By exploiting the autofluorescence of STF-62247, we pinpointed its cellular localization to lysosomes. Finally, in response to prolonged STF treatments, we show that VHL-proficient cells are able to surmount the block in late stages of autophagy by restoring their lysosome numbers. Conversely, an increase in autophagic vesicles accompanied by a time-dependent decrease in lysosomes was observed in VHL-deficient cells. This is the first mechanistic study investigating STF-62447’s effects on the autophagic flux in RCC. Importantly, our study reclassifies STF-62247 as a blocker of later stages of autophagy and highlights the possibility of blocking this process through lysosome disruption in VHL-mutated RCCs. |
Databáze: | OpenAIRE |
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