Yang Eric, Boire Adrienne, Agarwal Anika, Nguyen Nga, O'Callaghan Katie, Tu Powen, Kuliopulos Athan, Covic Lidija
Division of Hematology/Oncology, Molecular Oncology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Cancer Res. 2009 Aug 1;69(15):6223-31. doi: 10.1158/0008-5472.CAN-09-0187. Epub 2009 Jul 21.
Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that is not expressed in normal breast epithelia but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide "pepducin," P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and Taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor showed attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and Taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with Taxotere alone in advanced, metastatic breast cancer.
蛋白酶激活受体1（PAR1）是一种G蛋白偶联受体，在正常乳腺上皮细胞中不表达，但在浸润性乳腺癌中上调。在本研究中，我们发现基质金属蛋白酶-1（MMP-1）能强烈激活乳腺癌细胞中的PAR1-Akt存活通路。这一过程被一种细胞穿透性脂肽“pepducin”P1pal-7阻断，P1pal-7是表达PAR1的乳腺癌细胞中细胞活力的有效抑制剂。MMP-1抑制剂和P1pal-7均能显著促进乳腺肿瘤异种移植中的细胞凋亡，并将肺转移抑制高达88%。P1pal-7和多西他赛联合治疗可使MDA-MB-231异种移植瘤的生长抑制95%。同样，对用P1pal-7或MMP-1抑制剂治疗的异种移植瘤进行生化分析显示Akt活性减弱。组成型活性Akt的异位表达可使乳腺癌细胞免受P1pal-7和多西他赛的协同细胞毒性作用，表明Akt是PAR1依赖性癌细胞活力的关键组成部分。总之，这些发现表明，阻断MMP1-PAR1信号通路可能在晚期转移性乳腺癌中提供比单独使用多西他赛治疗更大的益处。
