Abstract
Cathepsin S (CTSS), a lysosomal cysteine protease, is overexpressed in various cancers, including glioblastoma (GB). A high level of CTSS is associated with tumor progression and poor outcome in GB. However, the underlying mechanisms of its role in the biological characteristics of G5B remain to be elucidated. Here, we uncovered a potential role of CTSS in the lysosomes and mitochondria of GB cells (GBCs). Downregulation of CTSS in GBCs could increase the expression of autophagy-related proteins; however, there was no significant change in p62, suggesting autophagy blockade. Moreover, inhibition of CTSS increased the expression of mitochondrial calcium uniporter (MCU) and enhanced mitochondrial Ca2+ uptake ability, causing mitochondrial Ca2+ overload, the generation of copious reactive oxygen species (ROS) and eventual mitochondrial apoptosis. Additionally, elevated damage to mitochondria exacerbated the burden of autophagy. Finally, we found that silence of MCU could alleviate the inhibition of CTSS-induced autophagosome accumulation and mitochondrial stress. Collectively, these results demonstrate that CTSS plays an important role in the process of autophagic flux and mitochondrial functions in GBCs.
Highlights
Glioma is the most common malignant brain cancer [1]
Cathepsin S (CTSS) mRNA expression was significantly higher in low grade glioma (LGG) and GB samples than in normal samples according to TGCA data (Figure 1A)
We found that inhibition of CTSS exert anti-tumor effects both in vitro and in vivo
Summary
Glioma is the most common malignant brain cancer [1]. Glioblastoma (GB) (or glioblastoma multiforme), which accounts for approximately 15% of all primary brain and central nervous system tumors and 55% of all gliomas, is regarded as the most aggressive and fatal type of glioma [2]. Due to the high progression and invasion capabilities and therapeutic resistance of GBs, patients with GBs have a 5-year survival rate of 5% [2]. Even when massive or total resection of the tumor is. From Lysosome to Mitochondria applied along with radiotherapy and chemotherapy, the prognosis of GB patients remains poor, with a median survival time of approximately 9–12 months [3]. Effective therapeutic strategies to improve GB patient prognosis should be developed. Cathepsin S (CTSS), a primarily lysosomal enzyme that can be found outside the lysosome, has a series of functions under extracellular conditions, unlike other family members [4]
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