Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-α/VEGF/Rho-GTPases: pivotal role of STAT-3.
Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-α/VEGF/Rho-GTPases: pivotal role of STAT-3.
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DOI：
10.1371/journal.pone.0025799
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Srivastava SK
中科院分区：
文献类型：
--
作者：
Boreddy SR;Sahu RP;Srivastava SK
我们以前的研究表明，异硫氰酸苄酯(BITC)通过抑制STAT-3抑制胰腺肿瘤的生长，但其确切的抑制肿瘤生长的机制尚不清楚。在此，我们探讨了BITC对胰腺肿瘤血管生成的影响及其机制。结果表明，BITC对大鼠主动脉和鸡绒毛膜尿囊膜新生血管有明显的抑制作用。此外，BITC还以剂量依赖的方式阻断BxPC-3和PANC-1胰腺癌细胞的迁移和侵袭。此外，BITC显著抑制常氧和低氧条件下BxPC-3和PANC-1细胞分泌血管内皮生长因子和基质金属蛋白酶-2。血管内皮生长因子和基质金属蛋白酶-2在肿瘤血管生成和转移中起重要作用。我们的结果显示，BITC显著抑制VEGFR-2(Tyr-1175)的磷酸化和HIF-α的表达。受血管内皮生长因子调控的Rho-GTP酶在胰腺癌的发展过程中起着至关重要的作用。BITC处理降低了RhoC的表达，上调了抑癌基因RhoB的表达。STAT-3过表达或IL-6处理可显著诱导HIF-1α和血管内皮生长因子的表达，但BITC显著抑制STAT-3和STAT-3诱导的HIF-1α和血管内皮生长因子的表达。最后，体内肿瘤生长和Matrigel-Plug试验显示，口服12微克分子BITC的小鼠肿瘤生长减少，Matrigel Plug和肿瘤中的血红蛋白含量显著减少，表明肿瘤血管生成减少。免疫印迹显示STAT-3磷酸化(TYR-705)、低氧诱导因子-α、血管内皮生长因子受体-2、血管内皮生长因子、基质金属蛋白酶-2、CD31和RhoC的表达减少。综上所述，我们的结果提示BITC通过STAT-3依赖的途径抑制肿瘤血管生成，从而抑制胰腺肿瘤的生长。
Our previous studies have shown that benzyl isothiocyanate (BITC) suppresses pancreatic tumor growth by inhibiting STAT-3; however, the exact mechanism of tumor growth suppression was not clear. Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis. Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken-Chorioallantoic membrane. Furthermore, BITC blocks the migration and invasion of BxPC-3 and PanC-1 pancreatic cancer cells in a dose dependant manner. Moreover, secretion of VEGF and MMP-2 in normoxic and hypoxic BxPC-3 and PanC-1 cells was significantly suppressed by BITC. Both VEGF and MMP-2 play a critical role in angiogenesis and metastasis. Our results reveal that BITC significantly suppresses the phosphorylation of VEGFR-2 (Tyr-1175), and expression of HIF-α. Rho-GTPases, which are regulated by VEGF play a crucial role in pancreatic cancer progression. BITC treatment reduced the expression of RhoC whereas up-regulated the expression of tumor suppressor RhoB. STAT-3 over-expression or IL-6 treatment significantly induced HIF-1α and VEGF expression; however, BITC substantially suppressed STAT-3 as well as STAT-3-induced HIF-1α and VEGF expression. Finally, in vivo tumor growth and matrigel-plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC, indicating reduced tumor angiogenesis. Immunoblotting of BITC treated tumors show reduced expression of STAT-3 phosphorylation (Tyr-705), HIF-α, VEGFR-2, VEGF, MMP-2, CD31 and RhoC. Taken together, our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through STAT-3-dependant pathway.
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影响因子：
4.9
作者：
Akhavani MA;Madden L;Buysschaert I;Sivakumar B;Kang N;Paleolog EM
通讯作者：
Paleolog EM
影响因子：
50.3
作者：
Mabjeesh, NJ;Escuin, D;Giannakakou, P
通讯作者：
Giannakakou, P
影响因子：
11.2
作者：
Cho SG;Yi Z;Pang X;Yi T;Wang Y;Luo J;Wu Z;Li D;Liu M
通讯作者：
Liu M
影响因子：
11.2
作者：
Maruyama, Yuichiro;Ono, Mayumi;Kuwano, Michihiko
通讯作者：
Kuwano, Michihiko
影响因子：
8
作者：
Oh, J;Takahashi, R;Noda, M
通讯作者：
Noda, M