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Imatinib disturbs lysosomal function and morphology and impairs the activity of mTORC1 in human hepatocyte cell lines

Roos, Noëmi Johanna and Mancuso, Riccardo Vincenzo and Sanvee, Gerda Mawududzi and Bouitbir, Jamal and Krähenbühl, Stephan. (2022) Imatinib disturbs lysosomal function and morphology and impairs the activity of mTORC1 in human hepatocyte cell lines. Food and Chemical Toxicology, 162. p. 112869.

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Abstract

The tyrosine kinase inhibitors (TKIs) imatinib and lapatinib are associated with severe hepatotoxicity, whose mechanisms are currently under investigation. As amphiphilic drugs, imatinib and lapatinib enrich in lysosomes. In the present study, we investigated their effects on lysosomal morphology and function in HepG2 and HuH-7 cells and explored possible links between lysosomal dysfunction and hepatotoxicity. Both TKIs increased the lysosomal volume time and concentration-dependently in HepG2 and HuH-7 cells. In HepG2 cells, lapatinib and imatinib raised the lysosomal pH and destabilized the lysosomal membrane, thereby impairing lysosomal proteolytic activity such as cathepsin B processing. Imatinib activated the transcription factor EB (TFEB), a regulator of lysosomal biogenesis and function, as demonstrated by nuclear TFEB accumulation and increased expression of TFEB-target genes. Because of lysosomal dysfunction, imatinib impaired mTORC1 activation, a protein complex activated on the lysosomal surface, which explained TFEB activation. HepG2 cells treated with imatinib showed increased levels of MAP1LC3A/B-II and of ATG13 (S318) phosphorylation, indicating induction of autophagy due to TFEB activation. Finally, imatinib induced apoptosis in HepG2 cells in a time and concentration-dependent manner, explained by lysosomal and mitochondrial toxicity. Our findings provide a new lysosome-centered mechanism for imatinib-induced hepatotoxicity that could be extended to other lysosomotropic drugs.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Bouitbir, Jamal and Roos, Noëmi Johanna and Mancuso, Riccardo and Sanvee, Mawududzi Gerda and Krähenbühl, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0278-6915
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:24 May 2022 03:10
Deposited On:30 Mar 2022 09:53

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