Targeting of cathepsin C induces autophagic dysregulation that directs ER stress mediated cellular cytotoxicity in colorectal cancer cells

Abstract As Autophagy is a pivotal mechanism of cancer cell survival and the development of chemotherapeutic resistance; therefore, new approaches are warranted for its targeting which may be fulfilled by cathepsins regulation. Amongst cathepsins, cathepsin C (CTSC) is highly expressed in various cancers and possesses significant therapeutic potential in autoimmune disorders; however, its role in colorectal cancer has not been explored. Herein, we aimed to investigate the role of CTSC in autophagy regulation mediated colorectal carcinoma cell proliferation. Cathepsin C targeting through inhibitors/siRNA leads to the accumulation of light chain 3 II and p62 without affecting the lysosomal integrity, revealed dysfunctional autolysosomal degradation which is also substantiated by proteolytic studies. Cathepsin C inhibition showed comparable autophagy blockade with E64d and augmented the autophagy blockade mediated by bafilomycin. Loss of CTSC function also induced ER stress-mediated JNK phosphorylation accompanied by the translocation of mitochondrial cyt c followed by apoptotic cell death in colorectal carcinoma cells. Taken together, the study reveals that CTSC targeting plays a key role in the regulation of autophagy mediated colorectal cancer cell proliferation. Further investigations are required to determine the functional role of CTSC in other tumors also which may have implications for the therapeutic prevention of cancer in the future.