Dasatinib inhibits c-src phosphorylation and prevents the proliferation of Triple-Negative Breast Cancer (TNBC) cells which overexpress Syndecan-Binding Protein (SDCBP).
Dasatinib inhibits c-src phosphorylation and prevents the proliferation of Triple-Negative Breast Cancer (TNBC) cells which overexpress Syndecan-Binding Protein (SDCBP).
复制标题
达沙替尼抑制 c-src 磷酸化并防止过度表达 Syndecan 结合蛋白 (SDCBP) 的三阴性乳腺癌 (TNBC) 细胞的增殖。
DOI：
10.1371/journal.pone.0171169
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Fu L
中科院分区：
文献类型：
--
作者：
Qian XL;Zhang J;Li PZ;Lang RG;Li WD;Sun H;Liu FF;Guo XJ;Gu F;Fu L
三阴性乳腺癌（TNBC）进展迅速，但缺乏有效的靶向治疗。我们以前的研究表明，下调Syndecan-binding protein（SDCBP）在TNBC中抑制TNBC细胞的增殖。达沙替尼是一种新型的c-src磷酸化小分子抑制剂。本研究的目的是研究SDCBP是否是指示TNBC是否适合达沙替尼治疗的潜在标志物。本研究应用免疫共沉淀法鉴定了SDCBP和c-src在TNBC细胞系中的相互作用。另外，使用免疫组织化学来研究SDCBP和酪氨酸-419磷酸化c-src（p-c-src-Y 419）在TNBC组织中的表达。然后构建SDCBP过表达MDA-MB-231细胞，以评估达沙替尼对SDCBP诱导的体外TNBC进展和裸小鼠肿瘤形成的影响。我们发现野生型SDCBP与c-src相互作用并促进c-src的磷酸化;这种磷酸化被达沙替尼完全阻断。缺乏PDZ结构域的SDCBP没有这种效果。在52例连续随机检测的TNBC病例中，SDCBP的表达与p-c-src-Y 419的表达一致，并与组织学分级或Ki-67水平呈正相关。SDCBP过表达显著加速了TNBC细胞系MDA-MB-231的增殖和细胞周期进展;这些作用可通过达沙替尼治疗来预防。然而，随后抑制p27表达部分恢复了TNBC细胞的增殖和活力。本研究的结果表明，SDCBP与c-src相互作用，调节TNBC细胞中的G1/S，并通过促进c-src在残基419处的酪氨酸磷酸化来增强肿瘤细胞增殖。达沙替尼抑制这种磷酸化并阻断SDCBP诱导的细胞周期进程。因此，SDCBP可能是识别适合达沙替尼治疗的TNBC病例的重要标志物。
Triple negative breast cancer (TNBC) progresses rapidly but lacks effective targeted therapies. Our previous study showed that downregulating syndecan-binding protein (SDCBP) in TNBC inhibits the proliferation of TNBC cells. Dasatinib is a new small-molecule inhibitor of c-src phosphorylation. The aim of this study was to investigate if SDCBP is a potential marker to indicate whether a TNBC is suitable for dasatinib therapy. This study applied co-immunoprecipitation to identify the interaction between SDCBP and c-src in TNBC cell lines. In addition, immunohistochemistry was used to investigate SDCBP and tyrosine-419 phosphorylated c-src (p-c-src-Y419) expression in TNBC tissues. SDCBP-overexpressing MDA-MB-231 cells were then constructed to evaluate the effects of dasatinib on SDCBP-induced TNBC progression in vitro and tumor formation in nude mice. We found wild-type SDCBP interacted with c-src and promoted the phosphorylation of c-src; this phosphorylation was completely blocked by dasatinib. SDCBP lacking the PDZ domain had no such effect. Among the 52 consecutive random TNBC cases examined, the expression of SDCBP was consistent with that of p-c-src-Y419, and positively correlated with histological grading or Ki-67 levels. SDCBP overexpression significantly accelerated the proliferation and cell cycle progression of the TNBC cell line MDA-MB-231; these effects were prevented by dasatinib treatment. However, the subsequent inhibition of p27 expression partially restored the proliferation and viability of the TNBC cells. The results of this study suggest that SDCBP interacts with c-src, regulates G1/S in TNBC cells, and enhances tumor cell proliferation by promoting the tyrosine phosphorylation of c-src at residue 419. Dasatinib inhibits such phosphorylation and blocks SDCBP-induced cell cycle progression. Therefore, SDCBP might be an important marker for identifying TNBC cases that are suitable for dasatinib therapy.