Aspirin suppresses breast cancer metastasis to lung by targeting anoikis resistance
Aspirin suppresses breast cancer metastasis to lung by targeting anoikis resistance
复制标题
阿司匹林通过针对失巢凋亡抵抗来抑制乳腺癌肺转移
DOI：
10.1093/carcin/bgab117
复制
发表时间：
2022-02-10
期刊：
影响因子：
4.7
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
--
作者：
Xu, Ruijie;Yan, Yongheng;Dong, Zigang
最近的临床证据表明，定期服用阿司匹林可以降低乳腺癌转移的风险，但其机制仍不清楚。对失巢凋亡的抵抗与恶性转化和转移有关。在这里，我们研究了阿司匹林是否可以通过针对失巢凋亡抵抗来预防乳腺癌转移至肺部。阿司匹林在体外使乳腺癌细胞对失巢凋亡敏感，并在体内降低循环肿瘤细胞和远处转移。从机制上讲，血栓素 A2 (TXA(2)) 途径被确定为阿司匹林在失巢致敏中的相关分子靶标。脱离后，转移性乳腺癌细胞中血栓素 A2 受体 (TP) 和血栓素 A2 合酶 1 (TBXAS1) 均上调，通过持续激活 Akt 赋予失巢凋亡抵抗力，从而促进乳腺癌转移至肺部。一致的是，在癌细胞中敲低 TP 或在小鼠中基因删除 TP 都可以防止体内肺转移。总的来说，TXA(2) 途径在失巢凋亡抵抗中发挥着关键作用，并可能作为乳腺癌转移化学预防的潜在靶点。[图表]。
Clinical evidence recently suggests that the regular use of aspirin is associated with a lower risk of breast cancer metastasis, but mechanisms remain unclear. Resistance to anoikis has been implicated in malignant transformation and metastasis. Here, we investigated whether aspirin might prevent breast cancer metastasis to lung by targeting anoikis resistance. Aspirin sensitized breast cancer cells to anoikis in vitro and lowered the circulating tumor cells as well as distant metastasis in vivo. Mechanistically, thromboxane A2 (TXA(2)) pathway was identified as the relevant molecular target for aspirin in anoikis sensitization. Upon detachment, both thromboxane A2 receptor (TP) and thromboxane A2 synthase 1 (TBXAS1) were up-regulated in metastatic breast cancer cells, conferred anoikis resistance through persistent activation of Akt, thereby facilitated breast cancer metastasis to lung. Consistently, either knockdown of TP in cancer cells or genetic deletion of TP in mice protected against lung metastasis in vivo. Collectively, TXA(2) pathway plays a critical role in anoikis resistance and might serve as potential target for chemoprevention of breast cancer metastasis.[GRAPHICS].