Department of Brain and Cognitive Science, DGIST, Republic of Korea; Core Protein Resources Center, DGIST, Daegu, Republic of Korea.
Division of Biotechnology, DGIST, Daegu, Republic of Korea.
Arch Biochem Biophys. 2020 Jul 30;688:108407. doi: 10.1016/j.abb.2020.108407. Epub 2020 May 12.
Prostate cancer has the highest incidence among men in advanced countries, as well as a high mortality rate. Despite the efforts of numerous researchers to identify a gene-based therapeutic target as an effective treatment of prostate cancer, there is still a need for further research. The cathepsin gene family is known to have a close correlation with various cancer types and is highly expressed across these cancer types. This study aimed at investigating the correlation between the cathepsin A (CTSA) gene and prostate cancer. Our findings indicated a significantly elevated level of CTSA gene expression in the tissues of patients with prostate cancer when compared with normal prostate tissues. Furthermore, the knockdown of the CTSA gene in the representative prostate cancer cell lines PC3 and DU145 led to reduced proliferation and a marked reduction in anchorage-independent colony formation, which was shown to be caused by cell cycle arrest in the S phase. In addition, CTSA gene-knockdown prostate cancer cell lines showed a substantial decrease in migration and invasion, as well as a decrease in the marker genes that promote epithelial mesenchymal transition (EMT). Such phenotypic changes in prostate cancer cell lines through CTSA gene suppression were found to be mainly caused by reduced p38 MAPK protein phosphorylation; i.e. the inactivation of the p38 MAPK cell signaling pathway. Tumorigenesis was also found to be inhibited in CTSA gene-knockdown prostate cancer cell lines when a xenograft assay was carried out using Balb/c nude mice, and the p38 MAPK phosphorylation was inhibited in tumor tissues. Thus, the CTSA gene is presumed to play a key role in human prostate cancer tissues through high-level expression, and the suppression of the CTSA gene leads to the inhibition of prostate cancer cell proliferation, colony formation, and metastasis. The mechanism, by which these effects occur, was demonstrated to be the inactivation of the p38 MAPK signaling pathway.
前列腺癌在发达国家男性中的发病率最高，死亡率也很高。尽管众多研究人员努力寻找基于基因的治疗靶点，以期有效治疗前列腺癌，但仍需要进一步研究。组织蛋白酶基因家族与多种癌症类型密切相关，在这些癌症类型中高度表达。本研究旨在探讨组织蛋白酶 A (CTSA) 基因与前列腺癌之间的相关性。我们的研究结果表明，与正常前列腺组织相比，前列腺癌患者组织中的 CTSA 基因表达水平显著升高。此外，在代表性的前列腺癌细胞系 PC3 和 DU145 中敲低 CTSA 基因，导致细胞增殖减少，锚定独立集落形成明显减少，这是由于 S 期细胞周期停滞引起的。此外，CTSA 基因敲低的前列腺癌细胞系迁移和侵袭能力显著下降，促进上皮间质转化 (EMT) 的标记基因表达也下降。通过 CTSA 基因抑制发现前列腺癌细胞系发生这种表型变化主要是由于 p38 MAPK 蛋白磷酸化减少，即 p38 MAPK 细胞信号通路失活。在使用 Balb/c 裸鼠进行异种移植实验时，也发现 CTSA 基因敲低的前列腺癌细胞系的肿瘤发生受到抑制，并且肿瘤组织中的 p38 MAPK 磷酸化受到抑制。因此，CTSA 基因通过高水平表达被认为在人前列腺癌组织中发挥关键作用，抑制 CTSA 基因导致前列腺癌细胞增殖、集落形成和转移的抑制。这些作用发生的机制被证明是 p38 MAPK 信号通路的失活。
