Overexpression of RGPR-p117 reveals anticancer effects by regulating multiple signaling pathways in bone metastatic human breast cancer MDA-MB-231 cells

IF 3.7 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY IUBMB Life Pub Date : 2025-01-08 DOI:10.1002/iub.2939
Masayoshi Yamaguchi, Tomiyasu Murata, Noriaki Shimokawa
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Abstract

The role of RGPR-p117, a transcription factor, which binds to the TTGGC motif in the promoter region of the regucalcin gene, in cell regulation remains to be investigated. This study elucidated whether RGPR-p117 regulates the activity of triple-negative human breast cancer MDA-MB-231 cells in vitro. The wild-type and RGPR-p117-overexpressing cancer cells were cultured in DMEM supplemented with fetal bovine serum. RGPR-p117 overexpression suppressed colony formation and growth of cancer cells. Stimulatory effects of epidermal growth factor on cell growth were blocked by RGPR-p117 overexpression. Wild-type cell proliferation was repressed by cell cycle and intracellular signaling inhibitors. These effects were not potentiated in transfectants. Overexpressed RGPR-p117 protected cancer cells against apoptosis inducers. Mechanistic results showed that RGPR-p117 overexpression decreased the expression of Ras, PI3-kinase, Akt, mitogen-activated protein kinase, and mTOR, which are involved in cell growth, while it elevated the levels of the cancer cell suppressor p53, Rb, p21, and regucalcin. Overexpression of RGPR-p117 suppressed cancer cell migration and adhesion. Interestingly, osteoblastic MC3T3-E1 cells or macrophage RAW264.7 cells involved in the bone microenvironment were impaired by coculture with MDA-MB-231 cells. The effects of cancer cells were blocked by transfection. Coculture with conditioned medium obtained from breast cancer cells repressed proliferation and enhanced the death of osteoblastic cells and macrophages. A TNF-α signaling inhibitor blocked these effects. Thus, overexpressed RGPR-p117 was found to suppress the activity of breast cancer cells by regulating various signaling processes, providing new insight into cellular signaling regulation.

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RGPR-p117的过表达通过调节骨转移性人乳腺癌MDA-MB-231细胞的多种信号通路揭示了其抗癌作用。
RGPR-p117是一种转录因子,它与regucalcin基因启动子区域的TTGGC基序结合,在细胞调控中的作用仍有待研究。本研究阐明了RGPR-p117是否在体外调控三阴性人乳腺癌MDA-MB-231细胞的活性。在添加胎牛血清的DMEM中培养野生型和过表达rgpr -p117的癌细胞。RGPR-p117过表达抑制肿瘤细胞集落形成和生长。表皮生长因子对细胞生长的刺激作用被RGPR-p117过表达阻断。细胞周期和细胞内信号抑制剂可抑制野生型细胞的增殖。这些效应在转染物中没有增强。过表达的RGPR-p117保护癌细胞免受凋亡诱导剂的影响。机制结果表明,RGPR-p117过表达降低了参与细胞生长的Ras、pi3激酶、Akt、丝裂原活化蛋白激酶和mTOR的表达,升高了癌细胞抑制因子p53、Rb、p21和regulalcin的水平。过表达RGPR-p117可抑制癌细胞的迁移和粘附。有趣的是,与MDA-MB-231细胞共培养后,参与骨微环境的成骨细胞MC3T3-E1细胞或巨噬细胞RAW264.7细胞受损。癌细胞的作用通过转染被阻断。与从乳腺癌细胞中获得的条件培养基共培养,抑制了成骨细胞和巨噬细胞的增殖,增强了它们的死亡。TNF-α信号抑制剂阻断了这些作用。因此,我们发现过表达的RGPR-p117通过调控多种信号过程抑制乳腺癌细胞的活性,为细胞信号调控提供了新的认识。
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来源期刊
IUBMB Life
IUBMB Life 生物-生化与分子生物学
CiteScore
10.60
自引率
0.00%
发文量
109
审稿时长
4-8 weeks
期刊介绍: IUBMB Life is the flagship journal of the International Union of Biochemistry and Molecular Biology and is devoted to the rapid publication of the most novel and significant original research articles, reviews, and hypotheses in the broadly defined fields of biochemistry, molecular biology, cell biology, and molecular medicine.
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