In Silico, In Vitro, and Clinical Investigations of Cathepsin B and Stefin A mRNA Expression and a Correlation Analysis in Kidney Cancer

Abstract

The cysteine protease Cathepsin B (CtsB) plays a critical role in multiple signaling pathways, intracellular protein degradation, and processing. Endogenous inhibitors regulate its enzymatic activity, including stefins and other cystatins. Recent data proved that CtsB is implicated in tumor extracellular matrix remodeling, cell invasion, and metastasis: a misbalance between cathepsins and their natural inhibitors is often considered a sign of disease progression. In the present study, we investigated CtsB and stefin A (StfA) expression in renal cell carcinoma (RCC). mRNA analysis unveiled a significant CTSB and STFA increase in RCC tissues compared to adjacent non-cancerogenic tissues and a higher CtsB expression in malignant tumors than in benign renal neoplasms. Further analysis highlighted a positive correlation between CtsB and StfA expression as a function of patient sex, age, tumor size, grade, lymph node invasion, metastasis occurrence, and survival. Alternative overexpression and silencing of CtsB and StfA confirmed the correlation expression between these proteins in human RCC-derived cells through protein analysis and fluorescent microscopy. Finally, the ectopic expression of CtsB and StfA increased RCC cell proliferation. Our data strongly indicated that CtsB and StfA expression play an important role in RCC development by mutually stimulating their expression in RCC progression.

Proteolytic Resistance Determines Albumin Nanoparticle Drug Delivery Properties and Increases Cathepsin B, D, and G Expression

“…Glutaraldehyde has a known toxicity profile on living cells [ 41 ]; however, it exerts it mostly during the cross-linking reaction and therefore it was mitigated by extensive washing steps performed prior to cell administration. We chose two cancer cell lines investigated for lysosomal protease (cathepsin) expression: 769-P human renal cancer cells [ 42 ] and SKBR3 human breast cancer cells [ 10 ]. Both the cell lines were treated with ANP loaded with Rhodamine 123, and we measured the decrease of the dye fluorescence within 2 weeks.…”

“…Interestingly, it was reported that CtsB has a slight effect on mature albumin in comparison with other cystein cathepsins [ 46 ] and CtsD [ 47 ]. In this scenario, future investigations on the expression of more enzymes and their natural inhibitors [ 42 ] could shed light on the specific activity of different cathepsins in degrading ANPs. The major outcomes in this work are shown in Figure 7 .…”

Role of Nivolumab in the Modulation of PD-1 and PD-L1 Expression in Papillary and Clear Cell Renal Carcinoma (RCC)

“…A protein implicated in the prevention of the cytotoxic effects of many drugs is cathepsin B [ 47 ]. Increased expression of cathepsin B in RCC indicates its role in tumor progression [ 48 ]. Our results show that even if Cath B is expressed and active (except in ACHN cells) in RCC, nivolumab did not influence the expression or activity of this protein.…”

Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways

“…It has been reported that low stefin A expression can promote the development of glioblastoma, breast cancer and head and neck cancer. However, CatB and stefin A can form a positive feedback loop during renal cell carcinoma progression in renal cell carcinoma [95]. Aberrant expression of stefin B is also associated with diseases.…”