Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma.
Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma.
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DOI：
10.1038/bjc.2014.342
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发表时间：
2014-07-29
影响因子：
8.8
通讯作者：
Bates, D. O.
中科院分区：
文献类型：
--
作者：
Gammons, M. V.;Lucas, R.;Dean, R.;Coupland, S. E.;Oltean, S.;Bates, D. O.
目前转移性黑色素瘤的治疗靶向于驱动生长的癌症突变（例如，维罗非尼）或基于免疫的疗法（例如，ipilimumab）。肿瘤进展还需要血管生成，血管生成受VEGF-A调节，VEGF-A本身选择性剪接形成两个同种型家族，促血管生成和抗血管生成。转移性黑色素瘤与促血管生成VEGF-A的剪接开关相关，先前显示受SRPK 1的SRSF 1磷酸化调节。在这里，我们展示了一种新的方法来防止血管生成靶向剪接因子激酶，在黑色素瘤中高度表达。我们使用RT-PCR，蛋白质印迹和免疫组织化学研究SRPK 1，SRSF 1和VEGF在肿瘤细胞中的表达，并在体内异种移植试验中研究SRPK 1的敲除和抑制。在葡萄膜和皮肤黑色素瘤细胞系中，SRPK 1高度表达，并且通过敲低或用药理学抑制剂抑制SRPK 1降低促血管生成VEGF表达，维持抗血管生成VEGF同种型的产生。药理学SRPK 1抑制剂和SRPK 1敲低均降低了体内人黑色素瘤的生长，但均不影响体外细胞增殖。这些结果表明，选择性阻断促血管生成亚型通过抑制剪接位点选择SRPK 1抑制剂减少黑色素瘤生长。SRPK 1抑制剂可用作治疗剂。
Current therapies for metastatic melanoma are targeted either at cancer mutations driving growth (e.g., vemurafenib) or immune-based therapies (e.g., ipilimumab). Tumour progression also requires angiogenesis, which is regulated by VEGF-A, itself alternatively spliced to form two families of isoforms, pro- and anti-angiogenic. Metastatic melanoma is associated with a splicing switch to pro-angiogenic VEGF-A, previously shown to be regulated by SRSF1 phosphorylation by SRPK1. Here, we show a novel approach to preventing angiogenesis—targeting splicing factor kinases that are highly expressed in melanomas. We used RT–PCR, western blotting and immunohistochemistry to investigate SRPK1, SRSF1 and VEGF expression in tumour cells, and in vivo xenograft assays to investigate SRPK1 knockdown and inhibition in vivo. In both uveal and cutaneous melanoma cell lines, SRPK1 was highly expressed, and inhibition of SRPK1 by knockdown or with pharmacological inhibitors reduced pro-angiogenic VEGF expression maintaining the production of anti-angiogenic VEGF isoforms. Both pharmacological SRPK1 inhibitors and SRPK1 knockdown reduced growth of human melanomas in vivo, but neither affected cell proliferation in vitro. These results suggest that selective blocking of pro-angiogenic isoforms by inhibiting splice-site selection with SRPK1 inhibitors reduces melanoma growth. SRPK1 inhibitors may be used as therapeutic agents.
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影响因子：
6
作者：
Beazley-Long, Nicholas;Hua, Jing;Donaldson, Lucy F.
通讯作者：
Donaldson, Lucy F.
影响因子：
45.3
作者：
Bedikian, Agop Y.;Millward, Michael;Haluska, Frank G.
通讯作者：
Haluska, Frank G.
DOI：
10.1074/jbc.m109.074930
发表时间：
2010-02-19
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Nowak DG;Amin EM;Rennel ES;Hoareau-Aveilla C;Gammons M;Damodoran G;Hagiwara M;Harper SJ;Woolard J;Ladomery MR;Bates DO
通讯作者：
Bates DO
DOI：
10.1158/1078-0432.ccr-11-1595
发表时间：
2011-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Lipson EJ;Drake CG
通讯作者：
Drake CG
影响因子：
4.1
作者：
Boyd, SR;Tan, D;Cree, IA
通讯作者：
Cree, IA