Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
Laboratory of Molecular Biology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Oncology. 2022;100(7):399-412. doi: 10.1159/000524303. Epub 2022 Mar 25.
Regucalcin plays a multifunctional role in the regulation of cellular function including metabolism, signaling process, and transcriptional activity in maintaining cell homeostasis. Downregulated expression or activity of regucalcin contributes to the development of malignancies in various types of human cancer. Survival of cancer patients, including metastatic prostate cancer, is prolonged with high expression of regucalcin in the tumor tissues.
We elucidate whether extracellular regucalcin conquers the growth, migration, invasion, and adhesion of metastatic human prostate cancer PC-3 and DU-145 cells.
Extracellular regucalcin (0.1, 1, and 10 nM) of physiologic levels (1 nM at human serum) inhibited colony formation and growth of PC-3 and DU-145 cells, while it did not have an effect on cell death. Repressive effects of extracellular regucalcin on the proliferation were not exhibited by the presence of inhibitors of the cell cycle, intracellular signaling process, and transcriptional activity, suggesting that the signals of extracellular regucalcin are transmitted to block cell growth. Furthermore, extracellular regucalcin (0.1, 1, or 10 nM) inhibited migration, invasion, and adhesion of PC-3 and DU-145 cells. Mechanistically, extracellular regucalcin (10 nM) decreased the levels of various signaling proteins including Ras, posphatidylinositol-3 kinase, mitogen-activated protein kinase, mechanistic target of rapamycin, RSK-2, caveolin-1, and integrin β1 in PC-3 cells.
Thus, extracellular regucalcin may play a suppressive role in growth, migration, invasion, and adhesion, which are involved in the metastatic activity of human prostate cancer cells, via affecting diverse signaling processes. This study may provide a new strategy in preventing metastatic prostate cancer with exogenous regucalcin.
钙网织蛋白在调节细胞功能方面发挥着多种功能，包括代谢、信号转导过程和转录活性，以维持细胞内稳态。钙网织蛋白表达或活性下调导致各种类型人类癌症的恶性肿瘤发展。在肿瘤组织中高表达钙网织蛋白可延长包括转移性前列腺癌在内的癌症患者的生存期。
我们阐明细胞外钙网织蛋白是否能克服转移性人前列腺癌 PC-3 和 DU-145 细胞的生长、迁移、侵袭和黏附。
生理水平（人血清中 1 nM）的细胞外钙网织蛋白（0.1、1 和 10 nM）抑制 PC-3 和 DU-145 细胞集落形成和生长，但对细胞死亡没有影响。细胞周期、细胞内信号转导和转录活性抑制剂的存在并没有显示细胞外钙网织蛋白对增殖的抑制作用，表明细胞外钙网织蛋白的信号被传递以阻止细胞生长。此外，细胞外钙网织蛋白（0.1、1 或 10 nM）抑制 PC-3 和 DU-145 细胞的迁移、侵袭和黏附。从机制上讲，细胞外钙网织蛋白（10 nM）降低了 PC-3 细胞中包括 Ras、磷酸肌醇-3 激酶、丝裂原激活蛋白激酶、雷帕霉素的机制靶点、RSK-2、窖蛋白-1 和整合素 β1 等多种信号蛋白的水平。
因此，细胞外钙网织蛋白可能通过影响多种信号转导过程，在生长、迁移、侵袭和黏附等方面发挥抑制作用，从而参与人前列腺癌细胞的转移活性。本研究可能为用外源性钙网织蛋白预防转移性前列腺癌提供新策略。
