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.

由于自噬是癌细胞存活和化疗耐药性发展的关键机制；因此，有必要针对组织蛋白酶的调控实现针对其靶标的新方法。在组织蛋白酶中，组织蛋白酶C（CTSC）在各种癌症中高度表达，并在自身免疫性疾病中具有重要的治疗潜力。然而，尚未探讨其在结直肠癌中的作用。在本文中，我们旨在研究CTSC在自噬调节介导的结直肠癌细胞增殖中的作用。通过抑制剂/ siRNA靶向组织蛋白酶C导致轻链3 II和p62的积累而不会影响溶酶体的完整性，揭示了功能异常的溶酶体降解，这也通过蛋白水解研究得到证实。组织蛋白酶C抑制显示出与E64d相当的自噬阻滞作用，并增强了由bafilomycin介导的自噬阻滞作用。CTSC功能的丧失还诱导内质网应激介导的JNK磷酸化并伴随线粒体细胞移位c随后大肠癌细胞中凋亡细胞死亡。两者合计，这项研究表明CTSC靶向在自噬介导的结直肠癌细胞增殖的调节中起着关键作用。需要进一步的研究来确定CTSC在其他肿瘤中的功能作用，这也可能对将来的癌症治疗产生影响。