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

Noëmi Johanna Roos; Riccardo Vincenzo Mancuso; Gerda Mawududzi Sanvee; Jamal Bouitbir; Stephan Krähenbühl

doi:10.1016/j.fct.2022.112869

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

Food Chem Toxicol. 2022 Apr:162:112869. doi: 10.1016/j.fct.2022.112869. Epub 2022 Feb 16.

Authors

Noëmi Johanna Roos¹, Riccardo Vincenzo Mancuso², Gerda Mawududzi Sanvee¹, Jamal Bouitbir³, Stephan Krähenbühl⁴

Affiliations

¹ Division of Clinical Pharmacology & Toxicology, University Hospital of Basel, Switzerland; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Switzerland.
² Division of Clinical Pharmacology & Toxicology, University Hospital of Basel, Switzerland; Division of Molecular Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Switzerland.
³ Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Switzerland.
⁴ Division of Clinical Pharmacology & Toxicology, University Hospital of Basel, Switzerland. Electronic address: stephan.kraehenbuehl@usb.ch.

PMID: 35182693
DOI: 10.1016/j.fct.2022.112869

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.

Keywords: Autophagy; HepG2 cells; Hepatotoxicity; TFEB; Tyrosine kinase inhibitors (TKI); mTORC1.