In this work we characterized the action of the lysosomotropic agent LeuLeuOMe using distinct cellular models as a model for defining the role of lysosomal cathepsins in apoptosis. LeuLeuOMe was found to induce lysosomal membrane permeabilization, resulting in release of lysosomal cathepsins that cleave the proapoptotic Bcl-2 family member Bid and degrade the antiapoptotic member Bcl-2, Bcl-xL, or Mcl-1. Since antiapoptotic Bcl-2 family members and IAP's are often upregulated in cancer, it can be suggested that lysosomal destabilization has a major potential in cancer treatment.
COBISS.SI-ID: 21719335
In this work we have critically evaluated the role of lysosomes and lysosomal cathepsins in three major types of cell death, apoptosis, necrosis and autophagy, although the latter is probably not a cell death mechanism, but a survival one. The article is based also on our previous results.
COBISS.SI-ID: 22640935
TNF is a cytokine known to be an important mediator of apoptosis and inflammation in a number of diseases. TNF apoptosis has been known to be critically dependent on caspases; however, it has been recently suggested that cysteine cathepsins might also be involved in the pathway. Based on the use of caspase inhibitors, TNF-alpha induced caspase-dependent apoptosis, accompanied by lysosomal destabilization and the release of cathepsins in the cytosol. However, use of cathepsin inhibitors E-64d and CA-074 revealed that cysteine cathepsins only marginally affect the progression of apoptosis.
COBISS.SI-ID: 22717479
Mice lacking Ctsb exhibited reduced cell proliferation in mammary carcinomas and their lung metastases. No Ctsb genotype-dependent difference in tumour cell death was observed in vivo or by treatment of isolated PyMT cancer cells with tumour necrosis factor-alpha. However, cancer cells lacking Ctsb exhibited significantly higher resistance to apoptosis induction by the lysosomotropic agent Leu-Leu-OMe.
COBISS.SI-ID: 21554983
In this work a small, but detecable nuclear localization of cathepsin B was observed. This was supported by biochemical data showing a proteolytically active variant of cathepsin B in nuclear fractions. We also demonstrated that cathepsin V, but not cathepsin L, was localized to the nucleus in HTh74 cells in peri-nucleolar patterns. As deduced from co-localization studies and in vitro degradation assays, we suggest that nuclear variants of cathepsins are involved in the development of thyroid malignancies through modification of DNA-associated proteins.
COBISS.SI-ID: 23800615