Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, K7L 3N6, Kingston, Ontario, Canada.
Expert Opin Ther Targets. 2022 Mar;26(3):217-231. doi: 10.1080/14728222.2022.2047178. Epub 2022 Mar 11.
Calpain-1 and calpain-2 are prototypical classical isoforms of the calpain family of calcium-activated cysteine proteases. Their substrate proteins participate in a wide range of cellular processes, including transcription, survival, proliferation, apoptosis, migration, and invasion. Dysregulated calpain activity has been implicated in tumorigenesis, suggesting that calpains may be promising therapeutic targets.
This review covers clinical and basic research studies implicating calpain-1 and calpain-2 expression and activity in tumorigenesis and metastasis. We highlight isoform specific functions and provide an overview of substrates and cancer-related signalling pathways affected by calpain-mediated proteolytic cleavage. We also discuss efforts to develop clinically relevant calpain specific inhibitors and spotlight the challenges facing inhibitor development.
Rationale for targeting calpain-1 and calpain-2 in cancer is supported by pre-clinical and clinical studies demonstrating that calpain inhibition has the potential to attenuate carcinogenesis and block metastasis of aggressive tumors. The wide range of substrates and cleavage products, paired with inconsistencies in model systems, underscores the need for more complete understanding of physiological substrates and how calpain cleavage alters their functions in cellular processes. The development of isoform specific calpain inhibitors remains an important goal with therapeutic potential in cancer and other diseases.
钙蛋白酶-1 和钙蛋白酶-2 是钙蛋白酶家族中典型的经典同工型，属于钙激活半胱氨酸蛋白酶。其底物蛋白参与广泛的细胞过程，包括转录、存活、增殖、凋亡、迁移和侵袭。钙蛋白酶活性失调与肿瘤发生有关，这表明钙蛋白酶可能是有前途的治疗靶点。
这篇综述涵盖了将钙蛋白酶-1 和钙蛋白酶-2 的表达和活性与肿瘤发生和转移联系起来的临床和基础研究。我们强调同工型的特异性功能，并提供受钙蛋白酶介导的蛋白水解切割影响的底物和与癌症相关的信号通路概述。我们还讨论了开发临床相关的钙蛋白酶特异性抑制剂的努力，并强调了抑制剂开发所面临的挑战。
靶向钙蛋白酶-1 和钙蛋白酶-2 治疗癌症的合理性得到了临床前和临床研究的支持，这些研究表明钙蛋白酶抑制有可能减弱致癌作用并阻止侵袭性肿瘤的转移。广泛的底物和切割产物，加上模型系统的不一致性，突出表明需要更全面地了解生理底物以及钙蛋白酶切割如何改变它们在细胞过程中的功能。开发同工型特异性钙蛋白酶抑制剂仍然是一个重要目标，具有治疗癌症和其他疾病的潜力。
