PAI-1 induces Src inhibitor resistance via CCL5 in HER2-positive breast cancer cells.
PAI-1 induces Src inhibitor resistance via CCL5 in HER2-positive breast cancer cells.
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DOI：
10.1111/cas.13593
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发表时间：
2018-06
期刊：
影响因子：
5.7
通讯作者：
Guan X
中科院分区：
文献类型：
--
作者：
Fang H;Jin J;Huang D;Yang F;Guan X
酪氨酸激酶Src在包括乳腺癌在内的多种肿瘤中过度表达和激活，并被认为促进癌症的形成和发展。Src抑制剂最近被开发出来，并已显示出在乳腺癌中单独使用或与抗HER2抗体或化疗联合使用的疗效。不幸的是，Src抑制剂的效力受到耐药性发展的限制。在我们的研究中，我们首次建立了Src抑制剂saracatinib耐药乳腺癌细胞系（SKBR‐3/SI），通过评估mRNA表达谱，我们发现与亲本细胞相比，saracatinib耐药细胞中的纤溶酶原激活物抑制剂‐1 （PAI‐1）上调。进一步的研究表明，PAI‐1可能通过增加趋化因子（C‐C基序）配体5 （CCL5）的分泌来诱导乳腺癌细胞对萨拉卡替尼的耐药性。功能分析显示，PAI‐1和CCL5过表达促进了乳腺癌细胞的增殖和迁移，而抑制PAI‐1和CCL5则降低了saracatinib耐药细胞的增殖和迁移。我们还发现，靶向PAI‐1或CCL5可以逆转saracatinib耐药，这在临床环境中值得更多关注。
Tyrosine kinase Src is overexpressed and activated in various tumors, including breast cancer, and is supposed to promote cancer formation and development. Src inhibitors have been developed recently and have shown efficacy in breast cancer as a single agent or in combination with anti‐HER2 antibodies or chemotherapy. Unfortunately, the potency of Src inhibitor is limited by the development of drug resistance. In our study, we established an Src inhibitor saracatinib‐resistant breast cancer cell line (SKBR‐3/SI) for the first time and by evaluating mRNA expression profile, we found that plasminogen activator inhibitor‐1 (PAI‐1) was upregulated in saracatinib‐resistant cells compared to the parent cells. Further study demonstrated that PAI‐1 might induce saracatinib resistance in breast cancer cells by increasing the secretion of chemokine (C‐C motif) ligand 5 (CCL5). Functional assays showed that PAI‐1 and CCL5 overexpression promoted cell proliferation and migration in breast cancer cells, while inhibition of PAI‐1 and CCL5 decreased cell proliferation and migration in saracatinib‐resistant cells. We also showed that targeting PAI‐1 or CCL5 could reverse saracatinib resistance, which deserves more attention in clinical settings.
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影响因子：
3.7
作者：
Takeda T;Yamamoto H;Kanzaki H;Suzawa K;Yoshioka T;Tomida S;Cui X;Murali R;Namba K;Sato H;Torigoe H;Watanabe M;Shien K;Soh J;Asano H;Tsukuda K;Kitamura Y;Miyoshi S;Sendo T;Toyooka S
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影响因子：
11.2
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通讯作者：
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影响因子：
4
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Müller V
影响因子：
5.7
作者：
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影响因子：
64.8
作者：
Bild, AH;Yao, G;Nevins, JR
通讯作者：
Nevins, JR