Cathepsin S attenuates endosomal EGFR signalling: A mechanical rationale for the combination of cathepsin S and EGFR tyrosine kinase inhibitors

Abstract

EGF-mediated EGFR endocytosis plays a crucial role in the attenuation of EGFR activation by sorting from early endosomes to late endosomes and transporting them into lysosomes for the final proteolytic degradation. We previously observed that cathepsin S (CTSS) inhibition induces tumour cell autophagy through the EGFR-mediated signalling pathway. In this study, we further clarified the relationship between CTSS activities and EGFR signalling regulation. Our results revealed that CTSS can regulate EGFR signalling by facilitating EGF-mediated EGFR degradation. CTSS inhibition delayed the EGFR degradation process and caused EGFR accumulation in the late endosomes at the perinuclear region, which provides spatial compartments for prolonged EGFR and sustained downstream signal transducer and activator of transcription 3 and AKT signalling. Notably, cellular apoptosis was markedly enhanced by combining treatment with the EGFR inhibitor Iressa and CTSS inhibitor 6r. The data not only reveal a biological role of CTSS in EGFR signalling regulation but also evidence a rationale for its clinical evaluation in the combination of CTSS and EGFR tyrosine kinase inhibitors.

FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury

“…Ctss was not detected in uninjured kidney, but it was expressed in the outer segment of the outer medulla during injury (day 2), and expression even increased by day 14 day, as shown by ISH and qPCR. Ctss is involved in EGFR degradation (29); therefore, one can hypothesize that persistent upregulation of Ctss in the tubular epithelium may prevent further EGFR activation, which could potentially promote renal fibrosis as previously reported (30,31). Sprr2f belongs to the Sprr family of proteins, which are expressed at high levels in the epidermis and function to maintain epithelial integrity (32).…”

Induction of Tyrosine Phosphorylation of UV-Activated EGFR by the Beta-Human Papillomavirus Type 8 E6 Leads to Papillomatosis

“…For instance, EGFR endocytosis to early endosomes was found to be required for the full stimulation of EGF-induced ERK1/2 and PI3K/AKT signaling ( Vieira et al, 1996 ). Particularly, perinuclear endosomes have been shown to provide a spatial compartment for prolonged EGFR signaling ( Huang et al, 2016 ). Our data showing a co-localization of the UV-activated EGFR and CD63 predominantly at perinuclear regions in HPV8E6 N/TERTs may thus reflect a prolonged signaling.…”

“…A stimulation of the EGFR-mediated MAPK-Ras signaling pathway was suggested to occur from late endosomes and lysosomes as well ( Oksvold et al, 2001 ; Jiang and Sorkin, 2002 ; Fehrenbacher et al, 2009 ; German et al, 2011 ). Moreover, continuous EGFR signaling from late endosomes was shown to contribute to sustained downstream AKT and STAT3 activation and the endosomal accumulation of the activated EGFR increased tumor cell survival ( Huang et al, 2016 ).…”

Cathepsin S As an Inhibitor of Cardiovascular Inflammation and Calcification in Chronic Kidney Disease

“…This indicates that cathepsin S activity increases with CKD progression, suggesting that cathepsin S may be a therapeutic target to prevent cardiovascular complications in CKD. Huang et al ( 34 ) reveal a role of cathepsin S in epidermal growth factor receptors (EGFR) signaling regulation. EGFR expression has been reported as increased in various tumors of the bladder, colon, ovarian, and kidney.…”