Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
Department of Cosmetic Science, Kyungsung University, Busan, 48434, Republic of Korea.
Sci Rep. 2024 Oct 5;14(1):23218. doi: 10.1038/s41598-024-73578-3.
Breast cancer metastasis is associated with a poor prognosis and a high rate of mortality. Cathepsin L (CTSL) is a lysosomal cysteine protease that promotes tumor metastasis by degrading the extracellular matrix. Gene set enrichment analysis revealed that CTSL expression was higher in tumorous than in non-tumorous tissues of breast cancer patients and that high-level CTSL expression correlated positively with the epithelial-mesenchymal transition. Therefore, we hypothesized that inhibiting CTSL activity in tumor cells would prevent metastasis. In this study, we characterized the inhibitory activity of SnuCalCpI15, the I29 domain of a CTSL-like cysteine protease from Calotropis procera R. Br., and revealed that the propeptide stereoselectively inhibited CTSL in a reversible slow-binding manner, with an inhibitory constant (K) value of 1.38 ± 0.71 nM, indicating its potency as an exogenous inhibitor in anti-cancer therapy. SnuCalCpI15 was localized intracellularly in MDA-MB-231 breast cancer cells and suppressed tumor cell migration and invasion. These results demonstrate the potential of SnuCalCpI15 as a novel agent to prevent breast cancer metastasis.
乳腺癌转移与预后不良和死亡率高有关。组织蛋白酶 L（CTSL）是一种溶酶体半胱氨酸蛋白酶，通过降解细胞外基质促进肿瘤转移。基因集富集分析显示，CTSL 在乳腺癌患者的肿瘤组织中的表达高于非肿瘤组织，高水平的 CTSL 表达与上皮-间充质转化呈正相关。因此，我们假设抑制肿瘤细胞中的 CTSL 活性将阻止转移。在这项研究中，我们对 SnuCalCpI15（来自 Calotropis procera R. Br. 的 CTSL 样半胱氨酸蛋白酶的 I29 结构域）的抑制活性进行了表征，并揭示了前肽以立体选择性的方式以可逆的缓慢结合方式特异性抑制 CTSL，抑制常数（K）值为 1.38±0.71 nM，表明其作为抗癌治疗中外源抑制剂的效力。SnuCalCpI15 定位于 MDA-MB-231 乳腺癌细胞的细胞内，并抑制肿瘤细胞的迁移和侵袭。这些结果表明 SnuCalCpI15 有潜力成为预防乳腺癌转移的新型药物。
