Targeting lysosome function causes selective cytotoxicity in VHL-inactivated renal cell carcinomas
Autor: | Dominique Comeau, Nadia Bouhamdani, Kevin Cormier, Alexandre Coholan, Sandra Turcotte |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Cancer Research Tumor suppressor gene Carcinogenesis Pyridines Cell Antineoplastic Agents Apoptosis Biology urologic and male genital diseases medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Lysosome Autophagy Tumor Cells Cultured medicine Humans Cytotoxic T cell Carcinoma Renal Cell neoplasms Cell Proliferation Mutation Cell growth General Medicine Kidney Neoplasms female genital diseases and pregnancy complications Thiazoles 030104 developmental biology medicine.anatomical_structure Von Hippel-Lindau Tumor Suppressor Protein 030220 oncology & carcinogenesis Cancer research Lysosomes Clear cell |
Zdroj: | Carcinogenesis |
ISSN: | 1460-2180 0143-3334 |
Popis: | The inactivation of the tumor suppressor gene, von Hippel-Lindau (VHL), has been identified as the earliest event in renal cell carcinoma (RCC) development. The loss of heterogeneity by chromosome 3p deletion followed by inactivating mutations on the second VHL copy are events present in close to 90% of patients. Our study illustrates a lysosomal vulnerability in VHL-inactivated RCC in vitro. By investigating the mechanism of action of the previously identified STF-62247, a small bioactive compound known for its selective cytotoxic properties towards VHL-defective models, we present the promising approach of targeting truncal-driven VHL inactivation through lysosome disruption. Furthermore, by analyzing the open platform for exploring cancer genomic data (cbioportal), we uncover the high alteration frequency of essential lysosomal and autophagic genes in sequenced biopsies from clear cell RCC patient primary tumors. By investigating lysosome physiology, we also identify VHL-inactivated cells’ inability to maintain their lysosomes at the perinuclear localization in response to STF-62247-induced stress and accumulate cytoplasmic inclusion bodies in response to an inefficient lysosomal degradative capacity. Finally, by testing other known lysosomal-disrupting agents (LDAs), we show that these are selectively cytotoxic to cells lacking VHL functions. Our study builds a strong platform that could specifically link genetic clonal ccRCC evolution to lysosomal and trafficking vulnerabilities. |
Databáze: | OpenAIRE |
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