Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), 700 Tiverton Avenue, Los Angeles, CA, 90095-1732, USA.
Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, Yagotoyama 150, Tempaku, Nagoya, 468-8503, Japan.
Tissue Cell. 2020 Dec;67:101447. doi: 10.1016/j.tice.2020.101447. Epub 2020 Oct 23.
Regucalcin plays a multifunctional role in cell regulation as a suppressor in the processes of intracellular signaling and transcription, leading to inhibition of cell growth. The downregulated expression or activity of regucalcin has been shown to contribute to the development of carcinogenesis in various types of human cancer. The wild-type tumor suppressor TP53 gene encodes for a transcriptional factor p53. This protein may play a role in cell proliferation. Loss of p53 function may induce cell transformation during carcinogenesis and tumor progression of human cancer. We investigate whether or not extracellular regucalcin suppresses the proliferation of non-tumorigenic human mammary epithelial MCF 10A cells with loss of p53 in vitro. Loss of p53 did not impact colony formation and proliferation of the cells. Interestingly, p53 loss caused decrease in the cell cycle suppressor p21, but not retinoblastoma and regucalcin, as compared with those of wild-type MCF 10A cells. Notably, extracellular regucalcin suppressed colony formation and proliferation of wild-type MCF 10A cells and p53 (-/-) cells, while it did not have an effect on cell death. Mechanistically, extracellular regucalcin decreased levels of various signaling factors including Ras, phosphatidylinositol-3 kinase, mitogen-activated protein kinase (MAPK), phospho-MAPK, and signal transducer and activator of transcription 3 in wild-type MCF 10A cells and p53 (-/-) cells. Thus, extracellular regucalcin was found to suppress the growth of MCF 10A cells with loss of p53. Extracellular regucalcin may play a role as a suppressor in the growth of human mammary epithelial cells with p53 loss, providing a novel strategy for cancer.
Regucalcin 在细胞调节中发挥多功能作用，作为细胞内信号转导和转录过程的抑制剂，导致细胞生长抑制。下调 regucalcin 的表达或活性已被证明有助于各种类型的人类癌症的癌变发展。野生型肿瘤抑制基因 TP53 基因编码转录因子 p53。这种蛋白质可能在细胞增殖中发挥作用。p53 功能的丧失可能会在人类癌症的癌变和肿瘤进展过程中诱导细胞转化。我们研究了细胞外 regucalcin 是否会抑制体外具有 p53 缺失的非致瘤性人乳腺上皮 MCF 10A 细胞的增殖。p53 的缺失并不影响细胞的集落形成和增殖。有趣的是，与野生型 MCF 10A 细胞相比，p53 缺失导致细胞周期抑制剂 p21 减少，但视网膜母细胞瘤和 regucalcin 没有减少。值得注意的是，细胞外 regucalcin 抑制了野生型 MCF 10A 细胞和 p53（-/-）细胞的集落形成和增殖，而对细胞死亡没有影响。从机制上讲，细胞外 regucalcin 降低了各种信号因子的水平，包括 Ras、磷脂酰肌醇-3 激酶、丝裂原活化蛋白激酶 (MAPK)、磷酸化 MAPK 和信号转导和转录激活因子 3 在野生型 MCF 10A 细胞和 p53（-/-）细胞中。因此，发现细胞外 regucalcin 可抑制具有 p53 缺失的 MCF 10A 细胞的生长。细胞外 regucalcin 可能作为具有 p53 缺失的人乳腺上皮细胞生长的抑制剂发挥作用，为癌症提供了一种新的策略。
