Down-regulation of uPA and uPAR by 3,3'-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells.
Down-regulation of uPA and uPAR by 3,3'-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells.
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DOI：
10.1002/jcb.22323
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发表时间：
2009-11-01
影响因子：
4
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
--
作者：
Ahmad, Aamir;Kong, Dejuan;Wang, Zhiwei;Sarkar, Sanila. H.;Banerjee, Sanjeev;Sarkar, Fazlul H.
3，3 ′-二吲哚甲烷（DIM）是一种已知的抗乳腺癌和其他癌症的抗肿瘤药物;然而，其确切的作用机制仍不清楚。尿激酶型纤溶酶原激活物（uPA）及其受体（uPAR）系统参与了基底膜和细胞外基质的降解，导致肿瘤细胞的侵袭和转移。由于uPA-uPAR系统在侵袭性乳腺癌中高度激活，我们推测B-DIM的生物学活性可能是通过uPA-uPAR系统的失活介导的。我们发现B-DIM处理以及uPA-uPAR的沉默导致MDA-MB-231细胞的细胞生长和运动性的抑制，这部分是由于VEGF和MMP-9的抑制。此外，uPA-uPAR的沉默导致这些细胞对B-DIM的敏感性降低，表明uPA-uPAR在B-DIM介导的细胞生长和迁移抑制中起重要作用。我们还发现B-DIM对MCF-7细胞具有类似的作用，MCF-7细胞表达低水平的uPA-uPAR，这是由于MMP-9和VEGF的直接下调，而不依赖于uPA-uPAR系统。有趣的是，MCF-7细胞中uPA-uPAR的过表达减弱了B-DIM的抑制作用。因此，我们的结果表明，B-DIM下调uPA-uPAR在侵袭性乳腺癌中的表达，但在uPA-uPAR缺失的情况下，B-DIM可以直接抑制VEGF和MMP-9，从而抑制乳腺癌细胞的生长和迁移。
3,3′-Diindolylmethane (DIM) is a known anti-tumor agent against breast and other cancers; however, its exact mechanism of action remains unclear. The urokinase plasminogen activator (uPA) and its receptor (uPAR) system are involved in the degradation of basement membrane and extracellular matrix, leading to tumor cell invasion and metastasis. Since uPA-uPAR system is highly activated in aggressive breast cancer, we hypothesized that the biological activity of B-DIM could be mediated via inactivation of uPA-uPAR system. We found that B-DIM treatment as well as silencing of uPA-uPAR led to the inhibition of cell growth and motility of MDA-MB-231 cells, which was in part due to inhibition of VEGF and MMP-9. Moreover, silencing of uPA-uPAR led to decreased sensitivity of these cells to B-DIM indicating an important role of uPA-uPAR in B-DIM-mediated inhibition of cell growth and migration. We also found similar effects of B-DIM on MCF-7, cells expressing low levels of uPA-uPAR, which was due to direct down-regulation of MMP-9 and VEGF, independent of uPA-uPAR system. Interestingly, over-expression of uPA-uPAR in MCF-7 cells attenuated the inhibitory effects of B-DIM. Our results, therefore, suggest that B-DIM down-regulates uPA-uPAR in aggressive breast cancers but in the absence of uPA-uPAR, B-DIM can directly inhibit VEGF and MMP-9 leading to the inhibition of cell growth and migration of breast cancer cells.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
9.7
作者：
Hsu, Erin L.;Chen, Natalie;Hankinson, Oliver
通讯作者：
Hankinson, Oliver
影响因子：
5.7
作者：
Ali, Shadan;Banerjee, Sanjeev;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.
影响因子：
4.2
作者：
Heber, D;Bowerman, S
通讯作者：
Bowerman, S
影响因子：
4
作者：
Ahmad, Aamir;Banerjee, Sanjeev;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.